RNA Splicing Modulation

ABSTRACT

One aspect described herein is use of a compound to modulate the production of one or more mature RNA isoforms from a gene transcript in a cell. Another aspect described herein is use of a compound in a method to modulate exon inclusion or exon exclusion in one or more mature mRNA isoforms from a gene transcript in a cell.

PRIORITY CLAIM

This application claims priority to U.S. Provisional Application Ser.No. 62/956,616, filed Jan. 2, 2020, the entire contents of which ishereby incorporated by reference in its entirety.

JOINT RESEARCH AGREEMENT STATEMENT

This application is subject to a Joint Research Agreement betweenApplicant, The General Hospital Corporation, and Co-Applicant, PTCTherapeutics, Inc., which was in effect on or before the Jan. 2, 2020filing date of U.S. Provisional Application Ser. No. 62/956,616.

SEQUENCE LISTING

This application contains a Sequence Listing submitted electronically inASCII format, the entire contents of which is hereby incorporated byreference in its entirety.

INTRODUCTION

One aspect described herein is use of a compound to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell. Another aspect described herein is use of a compound in a methodto modulate exon inclusion or exon exclusion in one or more mature RNAisoforms from a gene transcript in a cell.

BACKGROUND

Splicing is a key control point in human gene expression. Disturbancesin splicing due to mutation or aberrant splicing regulatory networkslead to dysregulated protein expression and to a substantial fraction ofhuman diseases. These disturbances represent a promising opportunity fortherapeutic intervention. Several classes of active and selective smallmolecule splicing modulator compounds (SMCs) have recently beenidentified validating pre-mRNA splicing as a viable intervention point.However, to date there have been few examples of SMCs that effectivelytarget splicing defects and ameliorate pathogenesis.

RNA splicing is a complex and tightly regulated process that removesintrons from pre-mRNA transcripts to generate mature mRNA. Differentialprocessing of pre-mRNA is one of the principal mechanisms generatingdiversity in different cell and tissue types. This process can give riseto functionally different proteins or, can also generate mRNAs withdifferent localization, stability and efficiency of translation throughalternative splicing of UTRs. RNA splicing requires the widely conservedspliceosome machinery along with multiple splicing factors¹⁻². Thesplicing reaction is directed by specific sequences, including the 5′and 3′ splice sites, the intron branch site, and splice site enhancersand silencers found in both exons and introns¹⁻². Changes in thesequences of these elements, through inherited or sporadic mutations,can result in deficient or aberrant splice site recognition by thespliceosome and lead to mis-splicing of the pre-mRNA transcript.Disruption of splicing regulatory elements can generate aberranttranscripts through complete or partial exon skipping, intron inclusionor mis-regulation of alternative splicing, the outcome of which oftengenerates premature termination codons (PTCs) that lead tononsense-mediated mRNA decay (NMD) of the transcript or the productionof a truncated protein. Conversely, mutations in the UTRs may affecttranscript localization, stability or efficiency of translation.Mutations that alter mRNA splicing are known to lead to many humanmonogenic diseases including spinal muscular atrophy (SMA),neurofibromatosis type 1 (NF1), cystic fibrosis (CF), familialdysautonomia (FD), Duchenne muscular dystrophy (DMD) and myotonicdystrophy (DM), as well as steer to complex diseases such as cancer anddiabetes³⁻¹⁸.

The development of drugs that can increase the amount of normaltranscript in patients is a new, precisely targeted treatment approachaimed directly at the primary molecular disease mechanism withoutaltering the genome. The development of splicing modulation therapiesfor DMD (EXONDYS 51™) and SMA (Nusinersen, Risdiplam, Branaplam)⁴²⁻⁴³has validated the utility of splicing modification as a valuabletherapeutic strategy for human disorders.

New therapeutic approaches aimed at identifying and correcting pre-mRNAsplicing defects have shown significant promise in many diseases¹⁹⁻⁵⁵.Small molecule SMCs are attractive therapeutic options because they canbe orally administered and are typically systemic and thereforedistributed in all tissues. Advances in precision medicine and thecapability to discover patient-specific mutations have provided a strongimpetus to develop new methods to predict drug selectivity to a targetdisease gene of interest while improving the drug development processand enhancing patient safety in a personalized medicine paradigm.

SUMMARY

One aspect described herein is a compound for use in a method tomodulate the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith the compound, and wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,having the formula of Compound (I):

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a wildtype gene transcript comprising,three exons and two introns operably linked in the following order: Exon1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice siteof Exon 2 comprises, a sequence selected from the group consisting of:CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQID NO: 3), and CCAgtgagga (SEQ ID NO: 4).

Another aspect described herein is Compound (I) for use in the method,wherein the 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ IDNO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8).

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a mutant gene transcript comprising,three exons and two introns operably linked in the following order: Exon1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice siteof Exon 2 comprises, a sequence selected from the group consisting of:CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc(SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO:13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16).

Another aspect described herein is Compound (I) for use in the method,wherein the 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ IDNO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20),AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu(SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24).

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), andwherein N represents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), and wherein N representsany RNA nucleotide.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), and wherein N representsany RNA nucleotide.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, and wherein the method comprises, contacting the cell withCompound (I).

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon inclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, and wherein themethod comprises, contacting the cell with Compound (I).

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon exclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, and wherein themethod comprises, contacting the cell with Compound (I).

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, and wherein the method comprises, contacting the cell in vivo orin vitro with Compound (I).

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, and wherein the subject is human.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a wildtype gene transcript in a subject in need thereofcomprising, administering Compound (I) to the subject, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, and wherein one or more ofthe mature RNA isoforms produce a functional protein.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having the mutated transcript is selected from the groupconsisting of Table 14 and 15.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having the mutated transcript is selected from the groupconsisting of Table 14.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having the mutated transcript is other than the geneselected from the group consisting of Table 15.

One aspect described herein is use of a compound to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with the compound2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,having the formula of Compound (I):

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAgtaagt(SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO:3), and CCAgtgagga (SEQ ID NO: 4).

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAguaagu(SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO:7), and CCAgugagga (SEQ ID NO: 8).

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAgtaagc(SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO:11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13),ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16).

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAguaagc(SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO:19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21),AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), andAGUguaagua (SEQ ID NO: 24).

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27),CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30),TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33),TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36),TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39),GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42),AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51),TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54),GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57),CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60),AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63),and wherein N represents any DNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), and wherein Nrepresents any DNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell with Compound(I).

Another aspect described herein is use of Compound (I) to increase exoninclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I).

Another aspect described herein is use of Compound (I) to increase exonexclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I).

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell in vivo or invitro with Compound (I).

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript, andwherein the subject is human.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript, andwherein one or more of the mature RNA isoforms produce a functionalprotein.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering to the subject apharmaceutical composition of Compound (I) and a pharmaceuticallyacceptable carrier, excipient, or diluent, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript.

Another aspect described herein is use of Compound (I), wherein a genehaving the mutated transcript is selected from the group consisting ofTable 14 and 15.

Another aspect described herein is use of Compound (I), wherein a genehaving the mutated transcript is selected from the group consisting ofTable 14.

Another aspect described herein is use of Compound (I), wherein a genehaving the mutated transcript is other than the gene selected from thegroup consisting of Table 15.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1C: Differences Between Compound (I) and Kinetin

FIG. 1A shows the structure of kinetin compared with Compound (I).

FIG. 1B provides a representation of the dual-reporter minigene used totest splicing modulation activity of kinetin and Compound (I). Rluc andFluc indicate Renilla and Firefly luciferase, respectively. A/Cindicates the start codon mutation in Fluc and gtaagC (SEQ ID NO: 104)indicates the location of the mutation that results in exclusion of Exon20. Dose response curves for kinetin and Compound (I) are shown for thedual-luciferase assay in Rluc-FD-Fluc transfected HEK293T cells treatedfor 24 hours with kinetin or Compound (I). Exon 20 inclusion, measuredby normalized relative luciferase units (RLU), is plotted as a functionof compound concentration. Normalized RLU refers to the ratio betweenfirefly and Renilla luciferase and provides a measure of exon 20inclusion. Assays were run in triplicate and curves were created bynonlinear regression using Prism4 (GraphPad Software Inc.).

FIG. 1C shows Compound (I) splicing modulation activity in human FDfibroblasts. Cells were treated for 24 hours at the concentrationsindicated. The experiment was performed in triplicate.

FIGS. 2A-2G: Transcriptome Changes in Response to Compound (I).

FIG. 2A provides a representation of an exon triplet. Exon U is upstreamof Exon X, which is upstream of Exon D. R₁, R₂ and R₃ represent RNAsequencing (RNASeq) reads spanning the regions between two adjacentexons. UI₁, I₁X, XI₂ and I₂D are four regions flanking the four splicesites of the exon-triplet. Each flanking region consists of 25 exonicbase pairs and 75 intronic base pairs.

FIG. 2B provides a volcano plot showing the ψ (PSI: Percent Spliced-In)changes in splicing after treatment with Compound (I). Each dotrepresents one of the 161,097 expressed exon triplets in humanfibroblasts. The x axis represents the ψ changes after treatment and they axis represents the False Discovery Rate (FDR) (log 10 transformed).The two vertical dashed lines indicate ψ changes of 0.1 and −0.1 asthresholds for exclusion and inclusion, respectively. The horizontaldashed line indicates an FDR of 0.1. The dots on the right side of theright vertical dashed line and above the horizontal dashed linerepresent the exon-triplets with an increase for Exon X inclusion(Δψ≥0.1 and FDR<0.1) while the dots on left side of the left verticaldashed line and above the horizontal dashed line represent an increasefor Exon X exclusion (Δψ≤−0.1 and FDR<0.1). Black dots in-between thetwo vertical dashed lines represent exon-triplets unchanged from thetreatment.

FIG. 2C shows independent RT-PCR validation of splicing changes oftwenty randomly selected candidates after three independent experimentsrun in duplicate. For each validated exon-triplet, ψ change measured byRNASeq (x axis) is plotted against the splicing changes measured byRT-PCR (y axis). The R² value indicates the coefficient of Pearsoncorrelation. The solid line shows the estimated linear regression. Thegrey zone indicates the 95% confidence interval for predictions from theestimated linear regression.

FIGS. 2D-2G shows RT-PCR results comparing Compound (I) (Cpd(I)) andkinetin for the splicing response of the four highlighted genes in FIG.2C: LPINJ (FIG. 2D), HSD17B4 (FIG. 2E), SLC4A7 (FIG. 2F) and CRYZ (FIG.2G) in human fibroblasts. The upper bands indicate the isoform in whichExon X is included while the lower bands indicate the isoform in whichExon X is skipped.

FIGS. 3A-3G: Convolutional Neural Network (CNN) Prediction of Compound(I) Response

FIGS. 3A1-3A2 show a heatmap of 12 Motifs, with FIG. 3A1 showing CNNMotifs ranked according to predicted contribution in the CNN Modeltoward the inclusion Class (Motifs 25, 49 and 18), and Motifs rankedaccording to predicted contribution in the Model toward the exclusionClass (Motifs 47, 21, 29, 9 and 10), whereas FIG. 3A2 shows the Motifspredicted to contribute toward an unchanged response Class (Motifs 01,22, 27 and 37). The gradience bar indicates the directional contributionof each Motif used to build the dendrogram rows and columns representingthe predicted response of each Motif to treatment. The right domain(progressively darker shaded range from 0 to +1) indicates a Motifspredicted positive contribution while the left domain indicates a Motifspredicted negative contribution in a progressively darker shaded rangefrom 0 to −1. The LOGO plot for each Motif is shown on the left side ofthe heatmap with the corresponding Motif number shown on the right.

FIG. 3A3 shows a heatmap of positional importance for each of the 12Motifs from FIGS. 3A1-3A2 within the XI₂ region of the 5′ splice site ofExon X. The thick vertical line shows the exon-intron boundary. Thegradience bar indicates positional importance, as measured by positionalactivation in the first layer of the CNN Model, where the right positivedomain (shadowed-no slash) suggests the necessity of the Motif and theleft domain (shadowed-slash) suggests the absence of the Motif.

FIGS. 3B1-3B2 show a heatmap of 13 Motifs, with FIG. 3B1 showing theMotifs ranked according to predicted contribution in the CNN Modeltoward the inclusion Class (Motifs 25 and 49), and Motifs rankedaccording to predicted contribution in the model toward the exclusionClass (Motifs 10, 21, 47, 9 and 40), whereas FIG. 3B2 shows the Motifsranked according to predicted contribution in the model toward anunchanged response Class (Motifs 16, 33, 27, 35, 22 and 37). Thegradience bar indicates the directional contribution of each Motif usedto build the dendrogram rows and columns representing the predictedresponse of each Motif to treatment. The right domain (progressivelydarker shaded range from 0 to +1) indicates a Motifs predicted positivecontribution while the left domain (in a progressively darker shadedrange from 0 to −1) indicates a Motifs predicted negative contribution.The LOGO plot for each Motif is shown on the left side of the heatmapwith the corresponding Motif number shown on the right.

FIG. 3B3 shows a heatmap of positional importance for each of the 13Motifs from FIGS. 3B1-3B2 within the XI₂ region of the 5′ splice site ofExon X. The thick vertical line shows the exon-intron boundary. Thegradience bar indicates positional importance, as measured by positionalactivation in the first layer of the CNN model, where the right positivedomain (shadowed) suggests the necessity of the Motif and the leftdomain (progressively less shadowed) suggests the absence of the Motif.

FIG. 3C shows box plots indicating splicing strength for each splicejunction along the exon triplets for inclusion (light grey), exclusion(dark grey) and unchanged (black) group, as defined by the RNASeq databased on positional importance as shown in FIGS. 3A3 and 3B3. The middlelines inside the boxes indicate the median and the lower and upperhinges correspond to the first and third quartiles. Each box extends to1.5 times inter-quartile range (IQR) from upper and lower hingesrespectively. Outliers are not shown. Only comparisons with significantdifference are marked by stars (two-tailed, unpaired Welch's t test withBonferroni correction).

FIG. 3D shows the LOGO plot results of Enrichment Motifs from a 5-merenrichment analysis in adjacent nucleotides from the −3 to +7 positionof the 5′ splice sites of the middle exon, and shows their most similarCNN Motifs from the CNN Model having the same Class Effect (e.g.inclusion, exclusion and unchanged) beneath them. Enrichment MotifsAAGGT (SEQ ID NO: 110) and AGTAA (SEQ ID NO: 109) were enriched ininclusion Class sequences detected in the 5-mer enrichment analysis.These Enrichment Motifs looked similar to inclusion Class sequences forCNN Motif 25 (AAGGT) (SEQ ID NO: 43) and CNN Motif 49 (CTGTA) (SEQ IDNO: 63) identified by the CNN model, respectively. Similarly, EnrichmentMotif TTACA (SEQ ID NO: 105) was enriched in exclusion Class sequencesdetected in the 5-mer enrichment analysis. This Enrichment Motif lookedsimilar to the exclusion Class sequence for CNN Motif 29 (TCGTG) (SEQ IDNO: 47) identified by the CNN model. Enrichment Motif AGGTA (SEQ ID NO:106) was enriched in unchanged Class sequences detected in the 5-merenrichment analysis. This Enrichment Motif looked similar to theunchanged Class sequence for CNN Motif 22 (AGGAN)(SEQ ID NO: 41)identified by the CNN model.

FIGS. 3E-3G Upper row: The length of the exon triplets cloned intominigenes constructs are shown. The flanking sequences of the 5′ splicesites of Exon X are shown in LOGO plots. The height of each nucleotidewas estimated using in silico saturated mutagenesis, with thecorresponding closely matched CNN Motifs indicated below the plots. TheCPSF7 Minigene in FIG. 3E shows the wildtype 5′ splice site −6 to +6sequence GATTAAgtgggt (SEQ ID NO: 2), correlated with Motif 25: AAGGT(SEQ ID NO: 43) and compared with the mutated 5′ splice site −6 to +6sequence GATTAAGTAGGT (SEQ ID NO: 10), correlated with Motif 25: AAGGT(SEQ ID NO: 43) and Motif 49: CTGTA (SEQ ID NO: 63). The SETD5 Minigenein FIG. 3F shows the wildtype 5′ splice site −6 to +6 sequenceCACTAGgtgaga (SEQ ID NO: 3), correlated with Motif 10: TGAGC (SEQ ID NO:32) and Motif 21: GAGAG (SEQ ID NO: 40) and compared with the mutated 5′splice site −6 to +6 sequence CACTAGgtgagc (SEQ ID NO: 11), correlatedwith Motif 10: TGAGC (SEQ ID NO: 32). The PARP6 Minigene in FIG. 3Gshows the wildtype 5′ splice site −3 to +7 sequence CCAgtgagga (SEQ IDNO: 4), correlated with Motif 26: GATTA (SEQ ID NO: 44) and comparedwith the mutated 5′ splice site −3 to +7 sequence CCAgttagga (SEQ ID NO:12), correlated with Motif 32: TTAAA (SEQ ID NO: 49). Middle row:Splicing changes for Exon X in both wildtype and mutated exon triplets,predicted by the CNN model (left) and measured by RT-PCR of the minigene(right). The RT-PCR experiments were performed in duplicate andindependently repeated three times for each minigene to make the barplots (two-tailed, unpaired Student's t test). Bottom row: Example ofsplicing changes induced by treatment with Compound (I) in the minigenesplicing assays. The percentage for Exon X inclusion is indicatedbeneath each lane, from treated and untreated conditions in bothwildtype and mutated minigenes. The upper bands indicate the isoforms inwhich Exon X is included while the lower bands indicate the isoforms inwhich Exon X is skipped. The statistical significance, as shown in FIGS.3E-3G, was determined via two-tailed, unpaired Student's test: *p<0.05;**p<0.01; ***p<0.001.

FIGS. 4A-4F Identification of Compound (I) Targets

FIG. 4A shows the workflow for identification of potential therapeutictargets for Compound (I) as derived from ClinVar pathogenic mutations(CV-pMUTs). SpliceAI was applied to identify all ClinVar pathogenicmutations (CV-pMUTs) and the CNN model was used to determine whethercounts per million (CPMs) disrupting annotated splice sites would berescued by Compound (I) treatment (left). The bar plot shows thepercentage of each filtered result out of the total number of disruptingannotated splice sites (right).

FIG. 4B shows the violin plot of the distance from either all CV-pMUTsor the CV-pMUTs disrupting annotated splicing to the closest splicejunction. The y axis is in a log₁₀-transformed scale. Each violin shapeshows the distribution of distance. The horizontal dashed line indicates75 nucleotides from the closest splice junction. The significance ofdifference is determined using the Kolmogorov-Smirnov (K-S) test.

FIGS. 4C-4F Upper row: The sequences at the 5′ splice site of Exon X inpatient cells and minigene constructs are shown (FIGS. 4C-4F). Thesequences around the 5′ splice site of Exon X are shown in LOGO plots,with the closely matched CNN motifs indicated beneath the plots. TheLIPA patient cell minigene in FIG. 4C shows the cell line mutated 5′splice site −6 to +6 sequence AGCCAAgtaggc (SEQ ID NO: 107), correlatedwith Motif 25: AAGGT (SEQ ID NO: 43) and Motif 49: CTGTA (SEQ ID NO:63). The CFTR patient cell minigene in FIG. 4D shows the cell linemutated 5′ splice site −6 to +6 sequence ATCCAAgtatgt (SEQ ID NO: 14),correlated with Motif 25: AAGGT (SEQ ID NO: 43) and Motif 49: CTGTA (SEQID NO: 63). The MLH1 patient cell minigene in FIG. 4E shows the cellline mutated 5′ splice site −5 to +6 sequence CTGAAGtcagt (SEQ ID NO:15), correlated with Motif 18: AAGCT (SEQ ID NO: 38). The MAPT patientcell minigene in FIG. 4F shows the cell line mutated 5′ splice site −3to +16 sequence AGTgtgagtccttcacat (SEQ ID NO: 108), correlated withMotif 44: NTGNN (SEQ ID NO: 56) and Motif 38: TATGT (SEQ ID NO: 54). Thebar plots demonstrate the CNN model prediction of Compound (I) responsefor the mutated sequences. Middle row: RT-PCR experiments validatedtreatment responses in patient cell lines carrying specific splice sitemutations. The upper bands indicate the isoform in which the middle ExonX is included while the lower bands indicate the isoform in which themiddle Exon X is skipped. Each set of gels is one of the triplicatesused to generate the bar plots beneath. Bottom row: The bar plotsdemonstrate the splicing change promoted by Compound (I) treatment. Thestatistical significance, as shown in FIGS. 4C-4F, was determined viatwo-tailed, unpaired Student's test: *p<0.05; **p<0.01; ***p<0.001.

FIGS. 5A-5C CNN Model Training Process

FIGS. 5A1-5A2 show details of the CNN model workflow. For eachexon-triplet, as shown in FIG. 5A1, the sequences from UI₁, I₁X, XI₂ andI₂D are concatenated and then one-hot coded. In the model, two rounds ofconvolution were applied before the hidden layer. Each round ofconvolution consists of a convolution layer of fifty filters, a ReLUactivation layer and a max pooling layer of size 2. After two rounds ofconvolution, the output is converted connected to a hidden layer with90% dropout rate. The output from the hidden layer shown in FIG. 5A2 isReLU transformed again and is then linearly transformed into a vector ofthree, representing three different treatment responses. The finalsigmoid nonlinearity maps each element in the vector to a value between0 and 1, considered as the probability of Compound (I) responsiveness.

FIG. 5B shows the training progress of the CNN model. The x axisrepresents the number of Epochs iterated during training. The leftmost yaxis shows loss score measured by binary entropy while the rightmost yaxis shows the average AUC of prediction from three classes. Thevertical dashed midline at approximately 12 Epochs on the x axisindicates the stop of training to avoid overfitting. The light greynegative slope plot line shows training loss and the darker greynegative slope plot line shows validation loss respectively along thegrowth of Epochs shown on the x-axis. The positive slope black plot lineshows the improvement of AUC along the growth of Epochs shown on thex-axis.

FIG. 5C shows the AUC curves of prediction for each class using the testset. The x axis represents specificity while the y axis representssensitivity. The grey negative slope diagonal line indicates theboundary beneath which the prediction is no better than a random guess.The AUC for inclusion, exclusion and unchanged response are shown as therightmost grey plot line, the middle darker grey plot line and theleftmost black plot line adjacent to the grey diagonal line,respectively.

FIGS. 6A-6B: Motifs Identified by the CNN Model

FIGS. 6A1-6A7 show a heatmap of all CNN Motifs identified by the CNNModel. The color of the Drug Response Contribution in the gradience barindicates the directional contribution of each motif. The right sidedomain (progressively shaded in the darker range from 0 to +1) indicatespositive contribution while the left side domain (progressively shadedin the lighter range from 0 to −1) indicates negative contribution. TheLOGO plot of each motif is shown on the left side of the heatmap, withthe motif number shown on the right. The motif response is built inthree columns.

FIGS. 6A1-6A2 indicate a Class Effect, having contribution toward theinclusion Class (darker positive range in left column).

FIGS. 6A3-6A5 indicate a Class Effect, having contribution toward theexclusion Class (darker positive range in middle column).

FIGS. 6A6-6A7 indicate a Class Effect, having contribution toward anunchanged Class (darker positive range in right column).

FIGS. 6B1-6B4 show a heatmap of motif importance at each 100 nucleotidesin the UI₁, I₁X, XI₂ and I₂D regions, each of which consists of 25nucleotides in the exon and 75 nucleotides in the intron. Each thickvertical line shows the exon-intron boundary. The gradience barindicates positional importance, as measured by positional activation inthe first layer of the CNN model, where the right positive domain(shadowed) suggests the necessity of the motif and the left negativedomain (shadowed) suggests the absence of the motif. Only the top twelvemotifs are shown according to FIGS. 3A1-3A2. The motifs are groupedbased on their response classification, representing inclusion (Motifs18, 25 and 49), exclusion (Motifs 09, 10, 21, 29 and 47) and unchanged(Motifs 01, 22, 27 and 37).

FIGS. 7A-7G show the relative expression of full-length (FL) and Δ20ELP1 mRNA (left panel), and ELP1 protein quantification (right panel) inbrain (FIG. 7A) and liver (FIG. 7B) after oral doses of Compound (I)ranging from 10 to 100 mg/kg in adult transgenic TgFD9 mouse (n=4-6 micein each treatment group). Comparisons were done within the same group,against the vehicle-treated mice. In the figure, *p<0.05; **p<0.01;***p<0.001.

FIGS. 7C-E show the relative expression of full-length (FL) and Δ20 ELP1mRNA (left graphs), and ELP1 protein quantification (right graphs) inkidney (FIG. 7C), heart (FIG. 7D) and skin (FIG. 7E) after oral doses ofCompound (I) ranging from 10 to 100 mg/kg in adult transgenic TgFD9mouse (n=4-6 mice in each treatment group). Comparisons were done withinthe same group, against the vehicle-treated mice. FIG. 7F shows weightassessment of TgFD9 mice in different treatment groups. FIG. 7G showsCompound (I) distribution in the brain, liver, kidney and plasma. Thelevels of compound were measured using mass spectrometry. In the figure,*p<0.05; **p<0.01; ***p<0.001.

FIG. 8A shows a western blot analysis of LIPA protein in patientfibroblasts carrying the c.894G>A mutation. The top and bottom panelsshow the blot probed with anti-LIPA and anti-β-Actin antibody,respectively.

FIG. 8B shows a bar chart providing a densitometric analysis of thewestern blot expressed as percentage of wild-type (WT). LIPA wasnormalized to β-Actin. To generate the bar plot, the experiment wasperformed in duplicate and independently repeated three times. Thestatistical significance is determined via two-tailed, unpairedStudent's test: where * p<0.05; ** p<0.01; *** p<0.001.

FIG. 9A shows a western blot analysis of CFTR protein in 293-Flpin cellsstably expressing WT-EMG-i14-il8 or c.2988G>A-EMG-i14-il8. 293Flpincells with no endogenous expression of CFTR protein served as negativecontrol. The top and bottom panels show the blot probed with anti-CFTRand anti-Na+K+ATPase antibody, respectively.

FIG. 9B shows a bar plot providing a densitometric analysis of thewestern blot expressed as percentage of mature CFTR protein, Band C. Theamount of mature CFTR protein was normalized to Na+K+ATPase. To generatethe bar plot, the experiment was performed in duplicate andindependently repeated three times. the statistical significance isdetermined via two-tailed, unpaired Student's test: where * p<0.05; **p<0.01; *** p<0.001.

FIG. 9C shows CFTR chloride channel analysis in CFBE-Flpin cells stablyexpressing c.2988G>A-EMG-i14-i18 with a representative tracing ofshort-circuit current (Isc) measurements recorded in Ussing chambersafter treatment of cells with either DMSO (vehicle) or variable doses ofCompound (I) for 72 h, as indicated by the labeled dose levels for thetreatment response. Cells were mounted on Ussing chambers to measureCFTR mediated chloride channel. After stabilization of the basalcurrent, forskolin (10 μM) was added to the basolateral chambersfollowed by CFTR potentiator, Ivacaftor (10 μM), and CFTR Inhibitor 172(10 μM) added to the apical chambers.

FIG. 9D shows a stacked bar graph indicating recovery of CFTR functionupon treatment of cells with Compound (I). Change in Isc (ΔIsc), ameasure of CFTR function, was defined as the current inhibited byInh-172 after sustained Isc responses were achieved upon stimulationwith forskolin alone, indicated by a dark stack within each bar orsequentially with ivacaftor, indicated by a white stack within each bar(n=2 Isc measurements per treatment). The statistical significance isdetermined via one-way ANOVA when compared with forskolin stimulatedCFTR function in DMSO (vehicle) treated cells: where * p<0.05; **p<0.01; *** p<0.001.

FIGS. 10A-10F show the results of an in silico saturation mutagenesisanalysis on selected 100-mer portions of interrogated 400-mer sequencesof interest. The indices of the selected sequences in the XI₂ boundaryare provided. Each plot includes three parts: 1. The wild-type sequencewhere letter heights indicate the importance of each nucleotide: Thetaller the letter, the more important the wild-type nucleotide; 2. Aheatmap showing the changes of prediction score (probability of drugresponse) from the CNN Model when a nucleotide is mutated into the otherthree nucleotide alternatives: the darker the color, the stronger thechange of the prediction score; and, 3. A curve plot demonstrating thehighest gain (black line) and loss (grey line) of prediction score(probability of drug response) at each position. FIGS. 10A and 10Brepresent the XI₂ regions of two Motif sequences known to have aninclusion Class drug response, respectively. FIGS. 10C and 10D representthe XI₂ regions of two Motif sequences known to have an exclusion Classdrug response, respectively. FIGS. 10E and 10F represent the XI₂ regionsof two Motif sequences known to have an unchanged Class drug response,respectively. The results of this analysis on sequences known to have aparticular Class Effect confirm the usefulness of the CNN Model toaccurately predict and identify sequences capable of splicing modulationby a small molecule SMC.

FIG. 11 shows a heatmap of Pearson correlation between the EnrichmentMotif (each row) in adjacent nucleotides from the −3 to +7 position ofthe 5′ splice sites of the middle exon and 39 CNN motifs (each column).The range for positive and negative correlation is from 0 to 0.5 andfrom 0 to −0.5, respectively, where the lightest color indicates aneutral correlation and the progressively darker color toward a positiveor negative correlation indicates a progressively stronger correlation.For example, Enrichment Motif AAGGT (SEQ ID NO: 110), known to have anexon inclusion Effect, has the highest average Positive correlation toCNN Motifs (18, 25, 26, 28, 32 and 49) that have a predictivecontribution toward an exon inclusion Effect. Enrichment Motif TTACA(SEQ ID NO: 105), known to have an exon exclusion Effect, has thehighest average Positive correlation to CNN Motifs (01, 02, 03, 04, 05,09, 10, 12, 17, 20, 21, 29, 38, 40, 41, 42, 43, 44 and 47) that have apredictive contribution toward an exon exclusion Effect. EnrichmentMotif AGGTA (SEQ ID NO: 106), enriched in sequences known to have anunchanged exon Effect against drug treatment, has the highest averagecorrelation with CNN motifs (06, 14, 15, 16, 22, 23, 27, 31, 33, 34, 35,37, 46 and 48) for no treatment response. Comparatively, EnrichmentMotif AGTAA (SEQ ID NO: 109), known to have an exon inclusion Effect,has the highest average correlation with CNN motifs that are responsiblefor no drug response. This result suggests a potentially false-positiveEnrichment Motif detected during the enrichment analysis, where evenlydistributed nucleotides A, C, T and G were used as background. Notably,the human genome is biased towards the presence of GTAA (SEQ ID NO:169), in the +1 to +4 position of the 5′ splice site, thus suggestingEnrichment Motif AGTAA (SEQ ID NO: 109) is close to random. Theseobservations suggest the CNN Model is more capable of efficientlyidentifying motifs amenable to splicing modulation in the presence of asmall molecule SMC, with additional prediction power, than slowerclassical methods.

FIG. 12A shows the AUCs for the different treatment responses obtainedfrom 1,000 random-initiated CNN models. The diamond indicates theperformance of the CNN Model described herein.

FIG. 12B shows the distribution of Pearson correlation between theMotifs shown in FIGS. 3B1-3B2 in the CNN Model described herein andpredictive motifs having similar rates of probability in each of the1,000 random-initiated CNN models.

DETAILED DESCRIPTION

One aspect described herein is a compound for use in a method tomodulate the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith the compound, and wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,having the formula of Compound (I):

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a wildtype gene transcript comprising,three exons and two introns operably linked in the following order: Exon1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice siteof Exon 2 comprises, a sequence selected from the group consisting of:

(SEQ ID NO: 1) CAAgtaagt, (SEQ ID NO: 2) GATTAAgtgggt, (SEQ ID NO: 3)CACTAGgtgaga, and (SEQ ID NO: 4) CCAgtgagga.

Another aspect described herein is Compound (I) for use in the method,wherein the 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of:

(SEQ ID NO: 5) CAAguaagu, (SEQ ID NO: 6) GAUUAAgugggu, (SEQ ID NO: 7)CACUAGgugaga, and (SEQ ID NO: 8) CCAgugagga.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a mutant gene transcript comprising,three exons and two introns operably linked in the following order: Exon1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice siteof Exon 2 comprises, a sequence selected from the group consisting of:

(SEQ ID NO: 9) CAAgtaagc, (SEQ ID NO: 10) GATTAAgtaggt, (SEQ ID NO: 11)CACTAGgtgagc, (SEQ ID NO: 12) CCAgttagga, (SEQ ID NO: 13) AGCCAAgtatgt,(SEQ ID NO: 14) ATCCAAgtatgt, (SEQ ID NO: 15) CTGAAgtcagt, and(SEQ ID NO: 16) AGTgtaagta.

Another aspect described herein is Compound (I) for use in the method,wherein the 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of:

(SEQ ID NO: 17) CAAguaagc, (SEQ ID NO: 18) GAUUAAguaggu, (SEQ ID NO: 19)CACUAGgugagc, (SEQ ID NO: 20) CCAguuagga, (SEQ ID NO: 21) AGCCAAguaugu,(SEQ ID NO: 22) AUCCAAguaugu, (SEQ ID NO: 23) CUGAAgucagu, and(SEQ ID NO: 24) AGUguaagua.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), andwherein N represents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), and wherein N representsany RNA nucleotide.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), and wherein N representsany RNA nucleotide.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, and wherein the method comprises, contacting the cell withCompound (I).

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon inclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, and wherein themethod comprises, contacting the cell with Compound (I).

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon exclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, and wherein themethod comprises, contacting the cell with Compound (I).

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, and wherein the method comprises, contacting the cell in vivo orin vitro with Compound (I).

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, and wherein the subject is human,

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a wildtype gene transcript in a subject in need thereofcomprising, administering Compound (I) to the subject, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, and wherein one or more ofthe mature RNA isoforms produce a functional protein.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having the mutated transcript is selected from the groupconsisting of Table 14 and 15.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having the mutated transcript is selected from the groupconsisting of Table 14.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having the mutated transcript is other than the geneselected from the group consisting of Table 15.

One aspect described herein is use of a compound to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with the compound2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,having the formula of Compound (I):

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence selected from comprises, a sequence the groupconsisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2),CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4).

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8).

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagc (SEQ ID NO:9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11),CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt(SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO:16).

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagc (SEQ ID NO:17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19),CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu(SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO:24).

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence s nucleotide sequences of the predictedgene transcript are the 5′ splice site of Exon 2 is selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), and wherein Nrepresents any DNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell with Compound(I).

Another aspect described herein is use of Compound (I) to increase exoninclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I).

Another aspect described herein is use of Compound (I) to increase exonexclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I).

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell in vivo or invitro with Compound (I).

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript, andwherein the subject is human.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript, andwherein one or more of the mature RNA isoforms produce a functionalprotein.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering to the subject apharmaceutical composition of Compound (I) and a pharmaceuticallyacceptable carrier, excipient, or diluent, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript.

Another aspect described herein is use of Compound (I), wherein a genehaving a mutation in a gene transcript thereof is selected from thegroup consisting of Table 14 and 15.

Another aspect described herein is use of Compound (I), wherein a genehaving a mutation in a gene transcript thereof is selected from thegroup consisting of Table 14.

Another aspect described herein is use of Compound (I), wherein a genehaving a mutation in a gene transcript thereof is other than the geneselected from the group consisting of Table 15.

Methods of Modulating Wildtype Gene Isoforms

One aspect described herein is Compound (I) for use in a method tomodulate the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Table 1.

Table 1 lists wildtype genes identified by RNA sequencing and mutatedgenes predicted by SpliceAI scores and the CNN model, as describedherein, which may be modulated by Compound (I) toward either or bothexon inclusion and exon exclusion.

TABLE 1 A1BG-AS1, AAAS, ABCA1, ABCA4, ABCA6, ABCA9, ABCB6, ABCC3, ABCC9,ABHD14A-ACY1, ABI1, ABI2, ABI3BP, AC024560.3, AC027612.6, AC037459.4,ACAA1, ACACA, ACAD10, ACADSB, ACBD4, ACBD5, ACIN1, ACLY, ACOX1, ACSL3,ACSL4, ACTN1, ACY1, AD000671.6, ADA, ADAM10, ADAM33, ADAMTSL4, ADARB1,ADK, AFMID, AGK, AHI1, AKAP11, AKAP13, AKIP1, AKR1A1, AL163636.6,ALDH3A2, ALDH3B1, ALDH4A1, ALKBH1, ALKBH3, ALMS1, AMMECR1L, AMPD2, ANK2,ANKRD10, ANKRD11, ANKRD36, ANO6, ANTXR2, ANXA2, AP1G1, AP2M1, APBB2,APC, APOL1, APP, ARHGAP12, ARHGAP23, ARHGEF10, ARHGEF10L, ARHGEF12,ARHGEF25, ARID4B, ARIH2, ARMC9, ARSK, ASAH1, ASAP2, ASCC2, ASL, ASPH,ASPM, ASUN, ASXL1, ATG10, ATG16L1, ATG7, ATG9A, ATM, ATP2C1, ATP5SL,ATPAF1, ATRX, ATXN1, ATXN3, AUP1, AUTS2, AVL9, B3GALNT1, BAG6, BANP,BAX, BAZ1A, BBS4, BBS5, BBX, BCAR1, BCOR, BFSP1, BIN1, BIRC6, BLOC1S6,BMP2K, BMPR2, BOK, BPTF, BRCA1, BRCA2, BRD8, BRIP1, BROX, BTBD19,C11orf30, C11orf70, C12orf29, C16orf13, C1orf85, C1RL, C2CD5, C3orf18,C5orf42, C5orf45, C8orf59, C9orf156, C9orf85, CA5A, CA5BP1, CALU,CAMK2D, CAMTA1, CAPN3, CAPN7, CAPRIN2, CARD8, CARKD, CASP3, CAST, CCBL2,CCDC25, CCDC90B, CCNDBP1, CCNL1, CD3D, CD44, CD46, CD55, CD99P1, CDAN1,CDC14B, CDC16, CDH1, CDH23, CDK16, CEP290, CERKL, CFTR, CHD3, CHD7,CHEK2, CHKB, CKLF, CLASP1, CLCN1, CLCN6, CLK1, CLMP, CLN3, CMC1, CNGB3,CNOT10, COG6, COL11A1, COL12A1, COL16A1, COL3A1, COL4A3, COL4A5, COL5A2,COL6A1, COL6A3, COL7A1, COPB2, COPS7A, COPS8, COQ6, COX20, CPEB2, CPSF7,CPT1C, CRAT, CREBBP, CRLS1, CRNDE, CRYZ, CSAD, CSTB, CTDSPL, CTNS, CTSK,CTU2, CUBN, CUTC, CWC25, CWC27, CYB561D2, CYBB, CYLD, CYP20A1, DAB2,DBT, DCAF10, DCAF11, DCAF17, DCAF8, DCP1A, DCUN1D5, DCX, DCX, DDB2,DGKA, DGKE, DGUOK, DHRSX, DIMT1, DIS3, DLG1, DMD, DMTF1, DNAH5, DNAH9,DNAJC19, DNAJC2, DNM1L, DNMT1, DOCK5, DOCK7, DPH3, DPY19L4, DRAM2,DSCR3, DTNBP1, DUSP11, DUSP22, DYNC2H1, DYNC2LI1, EBF3, EBP, EBPL, EDC3,EDEM2, EDRF1, EFEMP1, EHBP1, EHMT2, EIF4A2, EIF4E2, EIF4H, ELK1, ELN,ELOVL1, ENC1, ENOSF1, EP300, EPB41L1, EPB41L2, ERBB2IP, ERCC6, ERLEC1,ERMAP, ETHE1, EVC, EVI5L, F10, F13A1, F8, FAM104A, FAM111A, FAM134C,FAM149B1, FAM172A, FAM204A, FAM211A- AS1, FAM21C, FAP, FBN1, FBXL12,FBXL3, FBXO25, FBXW11, FGF5, FGFR1OP, FHL2, FIG4, FIP1L1, FLAD1, FLNA,FLT3, FN1, FNBP4, FNIP2, FOXN3, FRYL, FUT8, FXR2, FYN, G6PC, GAA, GAB1,GABPB2, GABRE, GABRG2, GALNS, GCK, GFPT2, GGCT, GIT2, GK, GLA, GLS,GNB5, GNPTAB, GOLGA4, GOLGB1, GOLT1B, GPR133, GPR143, GPR180, GPX4,GRHPR, GRIPAP1, GRN, GTF2I, GTF3A, GUCY2C, GUF1, GUSB, GYPA, HACL1,HAUS7, HBB, HCFC1R1, HDAC10, HDAC7, HECTD3, HERC3, HFE, HIPK3, HMGXB4,HNRNPA2B1, HNRNPD, HNRNPDL, HPS1, HSD17B4, HSF2, HUWE1, IDH1, IFT57,IFT88, IGF2BP2, IL15RA, IL36RN, INF2, ING4, INO80E, INPP1, IP6K2, IPO8,IQCB1, IRAK4, ISOC2, IST1, ITGB1BP1, KATNBL1, KDM4C, KDM5A, KDSR,KIAA0100, KIAA0586, KIAA1109, KIF14, KIF3A, KIT, KITLG, KLC1, KMT2D,KRIT1, KTN1, L3HYPDH, LACC1, LAMB3, LAMTOR3, LAS1L, LDLR, LENG8, LETMD1,LGALS8, LHCGR, LINC00963, LIPA, LMAN2L, LMNA, LMO7, LONRF1, LOXL3,LPHN2, LPIN1, LRCH3, LRRC28, LRRC32, LSM1, LTA4H, LTBP1, LTBP3, LTBP4,LUC7L, LYPLAL1, LYRM7, LZTFL1, MACF1, MADD, MAGOHB, MAN2C1, MAP3K3,MAP4K4, MAPK11, MAPK12, MAPKAP1, MAPT, MARK3, MBD5, MBNL1, MBOAT2,MCFD2, ME3, MED13, MED15, MEG3, MEGF6, METAP1, METTL14, MFF, MFSD12,MGEA5, MGST2, MINK1, MIR22HG, MKS1, MLF1, MLH1, MLLT6, MLST8, MMAB,MMP19, MORF4L2, MOSPD1, MPC1, MPDZ, MPI, MPV17, MRPL33, MSH2, MSRB3,MTCH2, MTM1, MTMR2, MTMR3, MTMR6, MTRR, MTSS1L, MYBL1, MYBPC3, MYCBP2,MYEF2, MYLK, MYNN, MYO18A, MYO19, MYO1B, MYO5A, MYO7A, NABP1, NADK2,NAE1, NBN, NEK1, NEO1, NEXN, NF1, NF2, NFE2L1, NIPA2, NIPBL, NLRC5,NLRX1, NPEPPS, NPHP1, NPR2, NPRL3, NR3C2, NRG1, NSD1, NSFL1C, NSMCE2,NSUN4, NT5C2, NUB1, NUP43, NUP62, NUPL2, NUTM2A-AS1, OARD1, OCA2, OCRL,ODF2, ODF2L, OFD1, OGT, OPTN, ORC6, ORMDL1, OS9, OSBPL8, OTC, OTOGL,PACRGL, PAFAH1B1, PAH, PAM, PARD3, PARL, PARN, PARP11, PARP6, PATL1,PCBP2, PCID2, PCM1, PCNXL2, PCNXL4, PCYT2, PDCD10, PDE4DIP, PDLIM2,PDZD11, PEAK1, PEX1, PEX11A, PEX5, PFDN1, PFDN6, PFKM, PHC3, PHKG2,PHLDB1, PI4KB, PIGG, PIGN, PIGT, PIK3C2A, PIKFYVE, PILRB, PIN1, PKIG,PLA2G12A, PLA2R1, PLAGL1, PLBD2, PMS2, PMS2P3, PNPLA8, PODNL1, POLG,POLR3GL, POMGNT1, PPAP2A, PPFIBP1, PPIL3, PPIP5K2, PPM1M, PPP1R12A,PPP1R21, PPP2R3C, PPP3CB, PPP3CC, PPP4C, PPP6R2, PPRC1, PPT1, PREB,PREPL, PRKAG1, PRMT2, PRMT7, PRPF39, PRPF40B, PRR16, PRR4, PRRX1, PRUNE,PSME4, PTEN, PTPN13, PTPN21, PTPN23, PTPN4, PTPRA, PVR, PXDN, QTRTD1,R3HCC1L, R3HDM4, RAB11FIP2, RABEPK, RAD1, RAD51B, RAD51C, RALGPS2, RALY,RB1, RBBP9, RBCK1, RBM41, RCOR3, REPS1, REV3L, RFWD2, RGL2, RGN, RHAG,RHBDD2, RHOBTB1, RHOT1, RIF1, RIPK2, RNASE4, RNF146, RNF170, RNF214,RNF216, RNF34, RNFT1, ROBO1, RP11- 1055B8.7, RP11-14N7.2, RP11-274B21.1,RP11-33B1.1, RP11-383H13.1, RP11-773D16.1, RP13-279N23.2, RPAIN, RPL7L1,RPP14, RPS6KB2, RRBP1, RSU1, RTEL1, RTEL1- TNFRSF6B, RTTN, RUFY2, RWDD1,RWDD2B, RWDD4, SBF1, SCMH1, SCN1A, SCN5A, SDCCAG8, SDHD, SEC31B,SECISBP2L, SEMA4F, SENP1, SENP6, SERAC1, SETD5, SETX, SFXN4, SGSM3,SH3D19, SHMT2, SIPA1L1, SLC10A7, SLC12A1, SLC15A4, SLC22A17, SLC25A17,SLC25A32, SLC25A36, SLC35A1, SLC35A3, SLC35D2, SLC37A3, SLC38A2,SLC38A6, SLC4A11, SLC4A7, SLC5A6, SLC7A6, SLC9B2, SLIT2, SLMAP, SLMO1,SLTM, SMAD5, SMARCA1, SMARCD1, SMC5, SMEK2, SMPDL3A, SMS, SMURF2,SNAPC5, SNED1, SNHG14, SNHG15, SNRNP70, SNRPA1, SNRPG, SNX10, SNX14,SNX21, SPAST, SPATA20, SPATA7, SPDL1, SPG11, SPPL2A, SPTA1, SPTAN1,SPTB, SRD5A2, ST6GALNAC6, ST7, STARD3NL, STARD5, STAT6, STK11, STK16,STK19, STK40, STRA13, STRADA, STRN3, STX16, STX16- NPEPL1, STX3, STXBP1,STXBP3, STYXL1, SUCO, SUGP2, SUGT1, SULF1, SUN2, SUPT20H, SYNGAP1,SYNRG, TAF1, TAF2, TANGO2, TARBP2, TAS2R14, TAZ, TBC1D14, TBC1D17,TBC1D25, TBC1D5, TBCK, TBPL1, TBX15, TCERG1, TCIRG1, TEAD2, TECTA, TEP1,TFDP1, TFDP2, TFPI, TFR2, TGFBR2, THAP6, THAP9-AS1, THBS3, THOC2, TIA1,TIAL1, TIMM17B, TIMM21, TJP2, TM7SF3, TMCO4, TMEM11, TMEM120A, TMEM126B,TMEM138, TMEM18, TMEM194A, TMEM234, TMEM260, TMEM39B, TMEM62, TMOD2,TMPRSS6, TMUB2, TMX3, TOM1, TP53, TP53INP1, TP53TG1, TPD52L1, TPD52L2,TPO, TPRA1, TPT1-AS1, TRAPPC12, TRAPPC2, TREX2, TRIM16, TRIM37, TRIM65,TRIO, TRIP10, TRIP12, TROVE2, TRPC1, TRPM4, TRPT1, TSEN15, TSR1, TSTD3,TUBG2, TULP3, TXNDC11, TXNL4A, TYR, U2AF1L4, UACA, UBA7, UBE2A, UBE2D1,UBN2, UBP1, UBQLN1, UFD1L, UNC5B, URGCP, UROD, USMG5, USP24, USP25,USP33, USP53, USP8, VAMP7, VCAN, VEZT, VMA21, VPS13B, VPS29, WBP1,WDFY2, WDR35, WDR73, XDTP53, XPC, YEATS2, YIPF1, YME1L1, YY1AP1,ZBTB8OS, ZC2HC1A, ZC3H11A, ZCCHC6, ZCCHC8, ZDHHC16, ZDHHC20, ZDHHC7,ZFAND1, ZFAND5, ZFAS1, ZMIZ1, ZMYM4, ZMYM5, ZNF160, ZNF207, ZNF248,ZNF280D, ZNF384, ZNF512, ZNF516, ZNF532, ZNF720, and ZZZ3.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a wildtype gene transcript comprising,three exons and two introns operably linked in the following order: Exon1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site ofExon 2 comprises, a sequence selected from the group consisting of:CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype genetranscript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein the 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ IDNO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a mutant gene transcript comprising,three exons and two introns operably linked in the following order: Exon1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site ofExon 2 comprises, a sequence selected from the group consisting of:CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc(SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO:13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript istranscribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein the 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ IDNO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20),AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu(SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutantgene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), wherein N represents any DNA nucleotide, and whereinthe predicted wildtype or mutant gene transcript is transcribed from agene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a wildtype gene transcript comprising,three exons and two introns operably linked in the following order: Exon1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site ofExon 2 comprises, a sequence selected from the group consisting of:GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga(SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribedfrom a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a wildtype gene transcript comprising,three exons and two introns operably linked in the following order: Exon1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site ofExon 2 comprises, a sequence selected from the group consisting of:GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga(SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribedfrom a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a mutant gene transcript comprising,three exons and two introns operably linked in the following order: Exon1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site ofExon 2 comprises, a sequence selected from the group consisting of:GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga(SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO:14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), andwherein the mutant gene transcript is transcribed from a gene selectedfrom Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a mutant gene transcript comprising,three exons and two introns operably linked in the following order: Exon1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site ofExon 2 comprises, a sequence selected from the group consisting of:GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga(SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO:22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), andwherein the mutant gene transcript is transcribed from a gene selectedfrom Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell with Compound(I), and wherein the gene transcript is transcribed from a gene selectedfrom Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon inclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon exclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell in vivo or invitro with Compound (I), and wherein the gene transcript is transcribedfrom a gene selected from Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein the subject is human, and wherein thegene is selected from Table 1.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein one or more of the mature RNA isoformsproduce a functional protein, and wherein the gene is selected fromTable 1.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell, andwherein the gene transcript is transcribed from a gene selected fromTable 1.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having a mutation in a gene transcript thereof isselected from the group consisting of Table 1.

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagc (SEQ ID NO:9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11),CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt(SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO:16), and wherein the mutant gene transcript is transcribed from a geneselected from Table 1.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagc (SEQ ID NO:17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19),CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu(SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO:24), and wherein the mutant gene transcript is transcribed from a geneselected from Table 1.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27),CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30),TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33),TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36),TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39),GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42),AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51),TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54),GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57),CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60),AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Table 1.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: GATTAAgtgggt (SEQ ID NO:2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 1.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: GAUUAAgugggu (SEQ ID NO:6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 1.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: GATTAAgtaggt (SEQ ID NO:10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12),AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt(SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutantgene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: GAUUAAguaggu (SEQ ID NO:18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20),AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu(SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutantgene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell with Compound(I), and wherein the gene transcript is transcribed from a gene selectedfrom Table 1.

Another aspect described herein is use of Compound (I) to increase exoninclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), and wherein thegene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to increase exonexclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), and wherein thegene transcript is transcribed from a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell in vivo or invitro with Compound (I), and wherein the gene transcript is transcribedfrom a gene selected from Table 1.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript,wherein the subject is human, and wherein the gene is selected fromTable 1.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript,wherein one or more of the mature RNA isoforms produce a functionalprotein, and wherein the gene is selected from Table 1.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering to the subject apharmaceutical composition of Compound (I) and a pharmaceuticallyacceptable carrier, excipient, or diluent, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, and wherein the gene is selected from Table 1.

Another aspect described herein is use of Compound (I), wherein a genehaving a mutation in a gene transcript thereof is selected from thegroup consisting of Table 1.

One aspect described herein is Compound (I) for use in a method tomodulate the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Table 2.

Table 2 lists wildtype genes identified by RNA sequencing and mutatedgenes predicted by SpliceAI scores and the CNN model, as describedherein, which may be modulated by Compound (I) toward both exoninclusion and exon exclusion.

TABLE 2 ASPH, BBS4, BPTF, BRCA1, BRIP1, CD46, CDC14B, COL6A3, DIS3, DMD,DNM1L, DRAM2, DYNC2H1, FAM172A, FBN1, FIP1L1, GIT2, GLS, KLC1, LMAN2L,LPHN2, MACF1, MAPT, MEG3, MFF, MLH1, MOSPD1, MSRB3, MTMR2, MYLK, MYNN,MYO5A, OPTN, OTC, RPAIN, SDCCAG8, SIPA1L1, SLC38A6, SUPT20H, TBCK,TSEN15, and ZNF207.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ IDNO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 2.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ IDNO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 2.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ IDNO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12),AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt(SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutantgene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ IDNO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20),AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu(SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutantgene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), wherein N represents any DNA nucleotide, and whereinthe predicted wildtype or mutant gene transcript is transcribed from agene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Table 2.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta(SEQ ID NO: 16), and wherein the mutant gene transcript is transcribedfrom a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua(SEQ ID NO: 24), and wherein the mutant gene transcript is transcribedfrom a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell with Compound(I), and wherein the gene transcript is transcribed from a gene selectedfrom Table 2.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon inclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon exclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in a method tomodulate exon inclusion or exon exclusion in one or more mature RNAisoforms from a gene transcript in a cell, wherein the method comprises,contacting the cell in vivo or in vitro with Compound (I), and whereinthe gene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is Compound (I) for use in a method totreat a disease associated with or mediated by a mutation in a genetranscript in a subject in need thereof, wherein the method comprises,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein the subject is human, and wherein thegene is selected from Table 2.

Another aspect described herein is Compound (I) for use in a method totreat a disease associated with or mediated by a mutation in a genetranscript in a subject in need thereof, wherein the method comprises,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein one or more of the mature RNA isoformsproduce a functional protein, and wherein the gene is selected fromTable 2.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell, andwherein the gene transcript is transcribed from a gene selected fromTable 2.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having a mutation in a gene transcript thereof isselected from the group consisting of Table 2.

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagc (SEQ ID NO:9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11),CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt(SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO:16), and wherein the mutant gene transcript is transcribed from a geneselected from Table 2.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagc (SEQ ID NO:17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19),CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu(SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO:24), and wherein the mutant gene transcript is transcribed from a geneselected from Table 2.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27),CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30),TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33),TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36),TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39),GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42),AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51),TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54),GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57),CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60),AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Table 2.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CTGAAgtcagt (SEQ ID NO:15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant genetranscript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CUGAAgucagu (SEQ ID NO:23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant genetranscript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell with Compound(I), wherein the gene transcript is transcribed from a gene selectedfrom Table 2.

Another aspect described herein is use of Compound (I) to increase exoninclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to increase exonexclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Table 2.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell in vivo or invitro with Compound (I), wherein the gene transcript is transcribed froma gene selected from Table 2.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript,wherein the subject is human, and wherein the gene is selected fromTable 2.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript,wherein one or more of the mature RNA isoforms produce a functionalprotein, and wherein the gene is selected from Table 2.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering to the subject apharmaceutical composition of Compound (I) and a pharmaceuticallyacceptable carrier, excipient, or diluent, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, and wherein the gene is selected from Table 2.

Another aspect described herein is use of Compound (I), wherein a genehaving a mutation in a gene transcript thereof is selected from thegroup consisting of Table 2.

One aspect described herein is Compound (I) for use in a method tomodulate the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Table 3.

Table 3 lists wildtype genes identified by RNA sequencing, as describedherein, that may be modulated by Compound (I) toward either or both exoninclusion and exon exclusion.

TABLE 3 A1BG-AS1, AAAS, ABCA1, ABCA6, ABCA9, ABCB6, ABCC3, ABHD14A-ACY1,ABI1, ABI2, ABI3BP, AC024560.3, AC027612.6, AC037459.4, ACAA1, ACACA,ACAD10, ACBD4, ACBD5, ACIN1, ACLY, ACOX1, ACSL3, ACSL4, ACTN1, ACY1,AD000671.6, ADA, ADAM33, ADAMTSL4, ADARB1, ADK, AFMID, AHI1, AKAP11,AKAP13, AKIP1, AKR1A1, AL163636.6, ALDH3B1, ALDH4A1, ALKBH1, ALKBH3,AMMECR1L, AMPD2, ANK2, ANKRD10, ANKRD11, ANKRD36, ANO6, ANXA2, AP1G1,AP2M1, APBB2, APOL1, APP, ARHGAP12, ARHGAP23, ARHGEF10, ARHGEF10L,ARHGEF12, ARHGEF25, ARID4B, ARIH2, ARSK, ASAP2, ASCC2, ASL, ASPH, ASUN,ASXL1, ATG10, ATG16L1, ATG7, ATG9A, ATP2C1, ATP5SL, ATPAF1, ATXN1,ATXN3, AUP1, AUTS2, AVL9, B3GALNT1, BAG6, BANP, BAX, BAZ1A, BBS4, BBS5,BBX, BCAR1, BCOR, BIN1, BIRC6, BLOC1S6, BMP2K, BOK, BPTF, BRD8, BROX,BTBD19, C11orf30, C11orf70, C12orf29, C16orf13, C1orf85, C1RL, C2CD5,C3orf18, C5orf42, C5orf45, C8orf59, C9orf156, C9orf85, CA5BP1, CALU,CAMK2D, CAMTA1, CAPN7, CAPRIN2, CARD8, CARKD, CASP3, CAST, CCBL2,CCDC25, CCDC90B, CCNDBP1, CCNL1, CD44, CD46, CD55, CD99P1, CDC14B,CDC16, CDK16, CEP290, CHD3, CHEK2, CHKB, CKLF, CLASP1, CLCN6, CLK1,CMC1, CNOT10, COL12A1, COL16A1, COL6A3, COPB2, COPS7A, COPS8, COQ6,COX20, CPEB2, CPSF7, CPT1C, CRAT, CREBBP, CRLS1, CRNDE, CRYZ, CSAD,CTDSPL, CUTC, CWC25, CYB561D2, CYLD, CYP20A1, DAB2, DBT, DCAF10, DCAF11,DCAF17, DCAF8, DCP1A, DCUN1D5, DDB2, DGKA, DHRSX, DIMT1, DIS3, DLG1,DMD, DMTF1, DNAJC19, DNAJC2, DNM1L, DNMT1, DOCK5, DOCK7, DPH3, DPY19L4,DRAM2, DSCR3, DTNBP1, DUSP11, DUSP22, DYNC2H1, EBPL, EDC3, EDEM2, EDRF1,EFEMP1, EHBP1, EHMT2, EIF4A2, EIF4E2, EIF4H, ELK1, ELN, ELOVL1, ENC1,ENOSF1, EPB41L1, EPB41L2, ERBB2IP, ERLEC1, ERMAP, ETHE1, EVC, EVI5L,FAM104A, FAM111A, FAM134C, FAM149B1, FAM172A, FAM204A, FAM211A-AS1,FAM21C, FAP, FBXL12, FBXL3, FBXO25, FBXW11, FGF5, FGFR1OP, FHL2, FIP1L1,FLAD1, FLNA, FN1, FNBP4, FNIP2, FOXN3, FRYL, FUT8, FXR2, FYN, GAB1,GABPB2, GABRE, GALNS, GFPT2, GGCT, GIT2, GK, GLS, GOLGA4, GOLGB1,GOLT1B, GPR133, GPR180, GRIPAP1, GTF2I, GTF3A, GUF1, GUSB, HACL1, HAUS7,HCFC1R1, HDAC10, HDAC7, HECTD3, HERC3, HIPK3, HMGXB4, HNRNPA2B1, HNRNPD,HNRNPDL, HPS1, HSD17B4, HSF2, HUWE1, IFT88, IGF2BP2, IL15RA, INF2, ING4,INO80E, INPP1, IP6K2, IPO8, IQCB1, IRAK4, ISOC2, IST1, ITGB1BP1,KATNBL1, KDM4C, KDM5A, KIAA0100, KIF3A, KITLG, KLC1, KTN1, L3HYPDH,LACC1, LAMTOR3, LAS1L, LENG8, LETMD1, LGALS8, LINC00963, LMAN2L, LMO7,LONRF1, LOXL3, LPHN2, LPIN1, LRCH3, LRRC28, LRRC32, LSM1, LTA4H, LTBP1,LTBP3, LTBP4, LUC7L, LYPLAL1, LYRM7, LZTFL1, MACF1, MADD, MAGOHB,MAN2C1, MAP3K3, MAP4K4, MAPK11, MAPK12, MAPKAP1, MARK3, MBD5, MBNL1,MBOAT2, ME3, MED13, MED15, MEG3, MEG3, MEGF6, METAP1, METTL14, MFF,MFSD12, MGEA5, MGST2, MINK1, MIR22HG, MKS1, MLF1, MLH1, MLLT6, MLST8,MMP19, MORF4L2, MOSPD1, MPDZ, MPI, MPV17, MRPL33, MSRB3, MSRB3, MTCH2,MTMR2, MTMR3, MTMR6, MTRR, MTSS1L, MYBL1, MYCBP2, MYEF2, MYLK, MYNN,MYO18A, MYO19, MYO1B, MYO5A, NABP1, NADK2, NAE1, NBN, NEK1, NEO1, NEXN,NF2, NFE2L1, NIPA2, NLRC5, NLRX1, NPEPPS, NPR2, NPRL3, NRG1, NSFL1C,NSMCE2, NSUN4, NT5C2, NUB1, NUP43, NUP62, NUPL2, NUTM2A-AS1, OARD1,OCRL, ODF2, ODF2L, OFD1, OPTN, ORMDL1, OS9, OSBPL8, PACRGL, PAM, PARD3,PARL, PARP11, PARP6, PATL1, PCBP2, PCID2, PCM1, PCNXL2, PCNXL4, PCYT2,PDE4DIP, PDLIM2, PDZD11, PEAK1, PEX1, PEX11A, PEX5, PFDN1, PFDN6, PFKM,PHC3, PHKG2, PHLDB1, PI4KB, PIGG, PIGN, PIGT, PIK3C2A, PIKFYVE, PILRB,PIN1, PKIG, PLA2G12A, PLA2R1, PLAGL1, PLBD2, PMS2P3, PNPLA8, PODNL1,POLR3GL, PPAP2A, PPFIBP1, PPIL3, PPIP5K2, PPM1M, PPP1R12A, PPP1R21,PPP2R3C, PPP3CB, PPP3CC, PPP4C, PPP6R2, PPRC1, PREB, PREPL, PRKAG1,PRMT2, PRPF39, PRPF40B, PRR16, PRR4, PRRX1, PRUNE, PSME4, PTPN13,PTPN21, PTPN23, PTPN4, PTPRA, PVR, PXDN, QTRTD1, R3HCC1L, R3HDM4,RAB11FIP2, RABEPK, RAD1, RALGPS2, RALY, RBBP9, RBCK1, RBM41, RCOR3,REPS1, REV3L, RFWD2, RGL2, RGN, RHBDD2, RHOBTB1, RHOT1, RIF1, RIPK2,RNASE4, RNF146, RNF170, RNF214, RNF34, RNFT1, ROBO1, RP11-1055B8.7,RP11- 14N7.2, RP11-274B21.1, RP11-33B1.1, RP11- 383H13.1, RP11-773D16.1,RP13-279N23.2, RPAIN, RPL7L1, RPP14, RPS6KB2, RRBP1, RSU1, RTEL1,RTEL1-TNFRSF6B, RUFY2, RWDD1, RWDD2B, RWDD4, SBF1, SCMH1, SDCCAG8,SEC31B, SECISBP2L, SEMA4F, SENP1, SENP6, SERAC1, SETD5, SETX, SFXN4,SGSM3, SH3D19, SHMT2, SIPA1L1, SLC15A4, SLC22A17, SLC25A17, SLC25A32,SLC25A36, SLC35A1, SLC35A3, SLC35D2, SLC37A3, SLC38A2, SLC38A6, SLC4A7,SLC5A6, SLC7A6, SLC9B2, SLIT2, SLMAP, SLMO1, SLTM, SMAD5, SMARCA1,SMARCD1, SMC5, SMEK2, SMPDL3A, SMURF2, SNAPC5, SNED1, SNHG14, SNHG15,SNRNP70, SNRPA1, SNRPG, SNX14, SNX21, SPATA20, SPATA7, SPDL1, SPPL2A,SPTAN1, ST6GALNAC6, ST7, STARD3NL, STARD5, STAT6, STK16, STK19, STK40,STRA13, STRADA, STRN3, STX16, STX16-NPEPL1, STX3, STXBP3, STYXL1, SUCO,SUGP2, SUGT1, SULF1, SUN2, SUPT20H, SYNRG, TAF1, TAF2, TANGO2, TARBP2,TAS2R14, TAZ, TBC1D14, TBC1D17, TBC1D25, TBC1D5, TBCK, TBPL1, TBX15,TCERG1, TEAD2, TEP1, TFDP1, TFDP2, TFPI, TGFBR2, THAP6, THAP9-AS1,THBS3, THOC2, TIA1, TIAL1, TIMM17B, TIMM21, TM7SF3, TMCO4, TMEM11,TMEM120A, TMEM126B, TMEM18, TMEM194A, TMEM234, TMEM260, TMEM39B, TMEM62,TMOD2, TMUB2, TMX3, TOM1, TP53INP1, TP53TG1, TPD52L1, TPD52L2, TPRA1,TPT1-AS1, TRAPPC12, TREX2, TRIM16, TRIM65, TRIO, TRIP10, TRIP12, TROVE2,TRPC1, TRPM4, TRPT1, TSEN15, TSR1, TSTD3, TUBG2, TULP3, TXNDC11, TXNL4A,U2AF1L4, UACA, UBA7, UBE2A, UBE2D1, UBN2, UBP1, UBQLN1, UFD1L, UNC5B,URGCP, USMG5, USP24, USP25, USP33, USP53, USP8, VAMP7, VCAN, VEZT,VPS29, WBP1, WDFY2, YEATS2, YIPF1, YME1L1, YY1AP1, ZBTB8OS, ZC2HC1A,ZC3H11A, ZCCHC6, ZCCHC8, ZDHHC16, ZDHHC20, ZDHHC7, ZFAND1, ZFAND5,ZFAS1, ZMIZ1, ZMYM4, ZMYM5, ZNF160, ZNF207, ZNF248, ZNF280D, ZNF384,ZNF512, ZNF516, ZNF532, ZNF720, and ZZZ3.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ IDNO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 3.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ IDNO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 3.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutated wildtype gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein themutated wildtype gene transcript comprises, three exons and two intronsoperably linked in the following order: Exon 1, Intron 1, Exon 2, Intron2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequenceselected from the group consisting of: CAAgtaagc (SEQ ID NO: 9),GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga(SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO:14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), andwherein the mutated wildtype gene transcript is transcribed from a geneselected from Table 3.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutated wildtype gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein themutated wildtype gene transcript comprises, three exons and two intronsoperably linked in the following order: Exon 1, Intron 1, Exon 2, Intron2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequenceselected from the group consisting of: CAAguaagc (SEQ ID NO: 17),GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga(SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO:22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), andwherein the mutated wildtype gene transcript is transcribed from a geneselected from Table 3.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), wherein N represents any DNA nucleotide, and whereinthe predicted wildtype gene transcript is transcribed from a geneselected from Table 3.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype gene transcript is transcribed from a gene selected from Table3.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype gene transcript istranscribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype gene transcript istranscribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: GATTAAgtgggt (SEQ ID NO: 2), and CACTAGgtgaga(SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtypegene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype genetranscript is transcribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutated wildtype gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein themutated wildtype gene transcript comprises, three exons and two intronsoperably linked in the following order: Exon 1, Intron 1, Exon 2, Intron2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequenceselected from: CTGAAgtcagt (SEQ ID NO: 15), and wherein the mutatedwildtype gene transcript is transcribed from a gene selected from Table3.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutated wildtype gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein themutated wildtype gene transcript comprises, three exons and two intronsoperably linked in the following order: Exon 1, Intron 1, Exon 2, Intron2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequenceselected from CUGAAgucagu (SEQ ID NO: 23), and wherein the mutatedwildtype gene transcript is transcribed from a gene selected from Table3.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell with Compound(I), and wherein the gene transcript is transcribed from a gene selectedfrom Table 3.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon inclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon exclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell in vivo or invitro with Compound (I), and wherein the gene transcript is transcribedfrom a gene selected from Table 3.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a wildtype gene transcript in a subject in need thereofcomprising, administering Compound (I) to the subject, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, wherein the subject ishuman, and wherein the gene is selected from Table 3.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a wildtype gene transcript in a subject in need thereofcomprising, administering Compound (I) to the subject, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, wherein one or more of themature RNA isoforms produce a functional protein, and wherein the geneis selected from Table 3.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell, andwherein the gene transcript is transcribed from a gene selected fromTable 3.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having a mutation in a gene transcript thereof isselected from Table 3.

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutated wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the mutated wildtype gene transcript comprises, three exonsand two introns operably linked in the following order: Exon 1, Intron1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAgtaagc(SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO:11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13),ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutated wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the mutated wildtype gene transcript comprises, three exonsand two introns operably linked in the following order: Exon 1, Intron1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAguaagc(SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO:19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21),AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), andAGUguaagua (SEQ ID NO: 24), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the predicted wildtype gene transcript includes anucleotide sequence selected from the group consisting of: CTTAG (SEQ IDNO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO:28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO:31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO:34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO:37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO:40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO:43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO:46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO:49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO:52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO:55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO:58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO:61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), wherein Nrepresents any DNA nucleotide, and wherein the predicted wildtype genetranscript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: GATTAAgtgggt (SEQ ID NO:2), and CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 3.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: GAUUAAgugggu (SEQ ID NO:6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 3.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutated wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the mutated wildtype gene transcript comprises, three exonsand two introns operably linked in the following order: Exon 1, Intron1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2comprises, a sequence selected from: CTGAAgtcagt (SEQ ID NO: 15), andwherein the mutated wildtype gene transcript is transcribed from a geneselected from Table 3.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutated wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the mutated wildtype gene transcript comprises, three exonsand two introns operably linked in the following order: Exon 1, Intron1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2comprises, a sequence selected from CUGAAgucagu (SEQ ID NO: 23), andwherein the mutated wildtype gene transcript is transcribed from a geneselected from Table 3.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell with Compound(I), wherein the gene transcript is transcribed from a gene selectedfrom Table 3.

Another aspect described herein is use of Compound (I) to increase exoninclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to increase exonexclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Table 3.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell in vivo or invitro with Compound (I), wherein the gene transcript is transcribed froma gene selected from Table 3.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a wildtype genetranscript in a subject in need thereof comprising, administeringCompound (I) to the subject, wherein exon inclusion or exon exclusion ismodulated in one or more mature RNA isoforms produced from the genetranscript, wherein the subject is human, and wherein the gene isselected from Table 3.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a wildtype genetranscript in a subject in need thereof comprising, administeringCompound (I) to the subject, wherein exon inclusion or exon exclusion ismodulated in one or more mature RNA isoforms produced from the genetranscript, wherein one or more of the mature RNA isoforms produce afunctional protein, and wherein the gene is selected from Table 3.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a wildtype genetranscript in a subject in need thereof comprising, administering to thesubject a pharmaceutical composition of Compound (I) and apharmaceutically acceptable carrier, excipient, or diluent, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, and wherein the gene isselected from Table 3.

Another aspect described herein is use of Compound (I), wherein a genehaving a mutation in a gene transcript thereof is selected from thegroup consisting of Table 3.

Methods of Modulating Mutated Gene Isoforms

One aspect described herein is Compound (I) for use in a method tomodulate the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Table 4.

Table 4 lists mutated genes predicted by SpliceAI scores and the CNNModel, as described herein, that may be modulated by Compound (I) towardeither or both exon inclusion and exon exclusion.

TABLE 4 ABCA4, ABCC9, ACADSB, ADAM10, AGK, ALDH3A2, ALMS1, ANTXR2, APC,ARMC9, ASAH1, ASPM, ATM, ATRX, BBS4, BFSP1, BMPR2, BRCA1, BRCA2, BRIP1,CA5A, CAPN3, CD3D, CDAN1, CDH1, CDH23, CERKL, CFTR, CHD7, CLCN1, CLMP,CLN3, CNGB3, COG6, COL11A1, COL3A1, COL4A3, COL4A5, COL5A2, COL6A1,COL7A1, CSTB, CTNS, CTSK, CTU2, CUBN, CWC27, CYBB, DCX, DGKE, DGUOK,DMD, DNAH5, DNAH9, DYNC2H1, DYNC2LI1, EBF3, EBP, EP300, ERCC6, F10,F13A1, F8, FBN1, FIG4, FLT3, FUT8, G6PC, GAA, GABRG2, GCK, GLA, GNB5,GNPTAB, GPR143, GPX4, GRHPR, GRN, GUCY2C, GYPA, HBB, HFE, IDH1, IFT57,IL36RN, KDSR, KIAA0586, KIAA1109, KIF14, KIT, KMT2D, KRIT1, LAMB3, LDLR,LHCGR, LIPA, LMNA, MAPT, MCFD2, MLH1, MMAB, MPC1, MSH2, MTM1, MYBPC3,MYO7A, NF1, NIPBL, NPHP1, NR3C2, NSD1, OCA2, OFD1, OGT, ORC6, OTC,OTOGL, PAFAH1B1, PAH, PARN, PDCD10, PIGN, PMS2, POLG, POMGNT1, PPT1,PRMT7, PTEN, RAD51B, RAD51C, RB1, RHAG, RNF216, RTTN, SCN1A, SCN5A,SDCCAG8, SDHD, SLC10A7, SLC12A1, SLC4A11, SMS, SNX10, SPAST, SPG11,SPTA1, SPTB, SRD5A2, STK11, STXBP1, SYNGAP1, TCIRG1, TECTA, TFR2,TGFBR2, TJP2, TMEM138, TMPRSS6, TP53, TPO, TRAPPC2, TRIM37, TYR, UROD,VMA21, VPS13B, WDR35, WDR73, and XPC.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutated wildtype gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein thenon-mutated wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutated wildtype gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein thenon-mutated wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ IDNO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12),AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt(SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutantgene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ IDNO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20),AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu(SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutantgene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), wherein N represents any DNA nucleotide, and whereinthe predicted mutant gene transcript is transcribed from a gene selectedfrom Table 4.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedmutant gene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted mutant gene transcript istranscribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted mutant gene transcript istranscribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16),and wherein the mutant gene transcript is transcribed from a geneselected from Table 4.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24),and wherein the mutant gene transcript is transcribed from a geneselected from Table 4.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell with Compound(I), and wherein the gene transcript is transcribed from a gene selectedfrom Table 4.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon inclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon exclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell in vivo or invitro with Compound (I), and wherein the gene transcript is transcribedfrom a gene selected from Table 4.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein the subject is human, and wherein thegene is selected from Table 4.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein one or more of the mature RNA isoformsproduce a functional protein, and wherein the gene is selected fromTable 4.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell, andwherein the gene transcript is transcribed from a gene selected fromTable 4.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having a mutation in a gene transcript thereof isselected from Table 4.

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutated wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the non-mutated wildtype gene transcript comprises, threeexons and two introns operably linked in the following order: Exon 1,Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon2 comprises, a sequence selected from the group consisting of: CAAgtaagt(SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO:3), and CCAgtgagga (SEQ ID NO: 4), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutated wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the non-mutated wildtype gene transcript comprises, threeexons and two introns operably linked in the following order: Exon 1,Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon2 comprises, a sequence selected from the group consisting of: CAAguaagu(SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO:7), and CCAgugagga (SEQ ID NO: 8), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagc (SEQ ID NO:9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11),CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt(SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO:16), and wherein the mutant gene transcript is transcribed from a geneselected from Table 4.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagc (SEQ ID NO:17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19),CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu(SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO:24), and wherein the mutant gene transcript is transcribed from a geneselected from Table 4.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted mutantgene transcript in a cell comprising, contacting the cell with Compound(I), wherein the predicted mutant gene transcript includes a nucleotidesequence selected from the group consisting of: CTTAG (SEQ ID NO: 25),NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31),TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34),TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43),GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46),TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49),AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55),NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58),NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61),ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted mutant gene transcript istranscribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: AGCCAAgtatgt (SEQ ID NO:13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript istranscribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: AGCCAAguaugu (SEQ ID NO:21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), andAGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript istranscribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell with Compound(I), wherein the gene transcript is transcribed from a gene selectedfrom Table 4.

Another aspect described herein is use of Compound (I) to increase exoninclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to increase exonexclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Table 4.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell in vivo or invitro with Compound (I), wherein the gene transcript is transcribed froma gene selected from Table 4.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript,wherein the subject is human, and wherein the gene is selected fromTable 4.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript,wherein one or more of the mature RNA isoforms produce a functionalprotein, and wherein the gene is selected from Table 4.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering to the subject apharmaceutical composition of Compound (I) and a pharmaceuticallyacceptable carrier, excipient, or diluent, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, and wherein the gene is selected from Table 4.

Another aspect described herein is use of Compound (I), wherein a genehaving a mutation in a gene transcript thereof is selected from thegroup consisting of Table 4.

Methods of Modulating Wildtype Gene Isoforms

One aspect described herein is Compound (I) for use in a method tomodulate the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Table 5.

Table 5 lists wildtype genes identified by RNA sequencing, as describedherein, that may be modulated by Compound (I) toward exon inclusion.

TABLE 5 ABI1, ABI2, AC027612.6, ACBD5, ACIN1, ACLY, ACOX1, ACSL3, AFMID,AHI1, AKAP13, AL163636.6, ANKRD11, ANXA2, AP1G1, ARHGAP12, ARHGEF10,ARSK, ASAP2, ASPH, ATG10, ATP2C1, ATP5SL, B3GALNT1, BANP, BBX, BPTF,BROX, C11orf30, C12orf29, C2CD5, C3orf18, C5orf45, C8orf59, C9orf156,CA5BP1, CALU, CAMTA1, CASP3, CCBL2, CD44, CD46, CDC14B, CDK16, CEP290,CLASP1, CLK1, CMC1, COL12A1, COL6A3, COPB2, COPS8, CPSF7, CREBBP, CYLD,DAB2, DCAF8, DCP1A, DCUN1D5, DIS3, DNAJC19, DNM1L, DOCK5, DPH3, DRAM2,EDEM2, EFEMP1, EIF4H, ENC1, EPB41L2, FAM172A, FAM21C, FBXL3, FGFR1OP,FIP1L1, FNBP4, FRYL, FUT8, FXR2, GGCT, GIT2, GLS, GTF2I, HNRNPA2B1,HNRNPDL, HSD17B4, HSF2, IL15RA, INF2, INO80E, INPP1, IP6K2, IQCB1,ITGB1BP1, KATNBL1, KDM5A, KLC1, KTN1, L3HYPDH, LGALS8, LMAN2L, LONRF1,LPHN2, LPIN1, LRCH3, LSM1, MACF1, MAGOHB, MAPKAP1, MARK3, MBNL1, ME3,MEG3, METAP1, MFF, MOSPD1, MSRB3, MTMR2, MYEF2, MYLK, MYNN, MYO18A,MYO1B, MYO5A, NABP1, NEO1, NF2, NPEPPS, NRG1, NSMCE2, NUP62, OCRL, OFD1,OPTN, OSBPL8, PARP6, PDE4DIP, PDZD11, PHC3, PHLDB1, PIGN, PIN1, PNPLA8,PPP3CB, PPP3CC, PREPL, PRPF39, PRRX1, PRUNE, QTRTD1, R3HCC1L, RALY,RBBP9, RBM41, REV3L, RFWD2, RNASE4, RNF34, RP11-14N7.2, RP11- 274B21.1,RPAIN, RRBP1, RWDD1, SDCCAG8, SETX, SH3D19, SIPA1L1, SLC15A4, SLC35A3,SLC38A6, SLTM, SMARCA1, SNRNP70, SPATA7, SPDL1, SPPL2A, ST6GALNAC6,STARD3NL, STK40, STRN3, SUCO, SUGP2, SUPT20H, SYNRG, TAF2, TBCK, TBPL1,TGFBR2, THAP9-AS1, TIA1, TIAL1, TIMM17B, TM7SF3, TMEM126B, TMEM18,TMEM234, TPD52L1, TPT1-AS1, TRIM16, TRIM65, TRIP12, TROVE2, TSEN15,TXNL4A, UBP1, USP33, USP8, VEZT, VPS29, ZC2HC1A, ZC3H11A, ZDHHC20,ZNF207, ZNF516, and ZNF532.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ IDNO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 5.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ IDNO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 5.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutated wildtype gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein themutated wildtype gene transcript comprises, three exons and two intronsoperably linked in the following order: Exon 1, Intron 1, Exon 2, Intron2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequenceselected from the group consisting of: CAAgtaagc (SEQ ID NO: 9),GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga(SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO:14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), andwherein the mutated wildtype gene transcript is transcribed from a geneselected from Table 5.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutated wildtype gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein themutated wildtype gene transcript comprises, three exons and two intronsoperably linked in the following order: Exon 1, Intron 1, Exon 2, Intron2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequenceselected from the group consisting of: CAAguaagc (SEQ ID NO: 17),GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga(SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO:22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), andwherein the mutated wildtype gene transcript is transcribed from a geneselected from Table 5.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), wherein N represents any DNA nucleotide, and whereinthe predicted wildtype gene transcript is transcribed from a geneselected from Table 5.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype gene transcript is transcribed from a gene selected from Table5.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype gene transcript istranscribed from a gene selected from Table 5.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype gene transcript istranscribed from a gene selected from Table 5.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: GATTAAgtgggt (SEQ ID NO: 2), and CCAgtgagga(SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribedfrom a gene selected from Table 5.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: GAUUAAgugggu (SEQ ID NO: 6), and CCAgugagga(SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribedfrom a gene selected from Table 5.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell with Compound(I), and wherein the gene transcript is transcribed from a gene selectedfrom Table 5.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon inclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 5.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon exclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 5.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell in vivo or invitro with Compound (I), and wherein the gene transcript is transcribedfrom a gene selected from Table 5.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a wildtype gene transcript in a subject in need thereofcomprising, administering Compound (I) to the subject, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, wherein the subject ishuman, and wherein the gene is selected from Table 5.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a wildtype gene transcript in a subject in need thereofcomprising, administering Compound (I) to the subject, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, wherein one or more of themature RNA isoforms produce a functional protein, and wherein the geneis selected from Table 5.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell, andwherein the gene transcript is transcribed from a gene selected fromTable 5.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having a mutation in a gene transcript thereof isselected from Table 5.

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutated wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the mutated wildtype gene transcript comprises, three exonsand two introns operably linked in the following order: Exon 1, Intron1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAgtaagc(SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO:11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13),ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutated wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the mutated wildtype gene transcript comprises, three exonsand two introns operably linked in the following order: Exon 1, Intron1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAguaagc(SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO:19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21),AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), andAGUguaagua (SEQ ID NO: 24), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the predicted wildtype gene transcript includes anucleotide sequence selected from the group consisting of: CTTAG (SEQ IDNO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO:28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO:31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO:34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO:37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO:40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO:43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO:46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO:49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO:52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO:55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO:58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO:61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), wherein Nrepresents any DNA nucleotide, and wherein the predicted wildtype genetranscript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: GATTAAgtgggt (SEQ ID NO:2), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype genetranscript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: GAUUAAgugggu (SEQ ID NO:6), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype genetranscript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell with Compound(I), wherein the gene transcript is transcribed from a gene selectedfrom Table 5.

Another aspect described herein is use of Compound (I) to increase exoninclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to increase exonexclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Table 5.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell in vivo or invitro with Compound (I), wherein the gene transcript is transcribed froma gene selected from Table 5.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a wildtype genetranscript in a subject in need thereof comprising, administeringCompound (I) to the subject, wherein exon inclusion or exon exclusion ismodulated in one or more mature RNA isoforms produced from the genetranscript, wherein the subject is human, and wherein the gene isselected from Table 5.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a wildtype genetranscript in a subject in need thereof comprising, administeringCompound (I) to the subject, wherein exon inclusion or exon exclusion ismodulated in one or more mature RNA isoforms produced from the genetranscript, wherein one or more of the mature RNA isoforms produce afunctional protein, and wherein the gene is selected from Table 5.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a wildtype genetranscript in a subject in need thereof comprising, administering to thesubject a pharmaceutical composition of Compound (I) and apharmaceutically acceptable carrier, excipient, or diluent, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, and wherein the gene isselected from Table 5.

Another aspect described herein is use of Compound (I), wherein a genehaving a mutation in a gene transcript thereof is selected from thegroup consisting of Table 5.

One aspect described herein is Compound (I) for use in a method tomodulate the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Table 6.

Table 6 lists wildtype genes identified by RNA sequencing, as describedherein, that may be modulated by Compound (I) toward exon exclusion.

TABLE 6 A1BG-AS1, AAAS, ABCA1, ABCA6, ABCA9, ABCB6, ABCC3, ABHD14A-ACY1,ABI3BP, AC024560.3, AC037459.4, ACAA1, ACACA, ACAD10, ACBD4, ACSL4,ACTN1, ACY1, AD000671.6, ADA, ADAM33, ADAMTSL4, ADARB1, ADK, AKAP11,AKIP1, AKR1A1, ALDH3B1, ALDH4A1, ALKBH1, ALKBH3, AMMECR1L, AMPD2, ANK2,ANKRD10, ANKRD36, ANO6, AP2M1, APBB2, APOL1, APP, ARHGAP23, ARHGEF10L,ARHGEF12, ARHGEF25, ARID4B, ARIH2, ASCC2, ASL, ASPH, ASUN, ASXL1,ATG16L1, ATG7, ATG9A, ATPAF1, ATXN1, ATXN3, AUP1, AUTS2, AVL9, BAG6,BAX, BAZ1A, BBS4, BBS5, BCAR1, BCOR, BIN1, BIRC6, BLOC1S6, BMP2K, BOK,BPTF, BRD8, BTBD19, C11orf70, C16orf13, C1orf85, C1RL, C5orf42, C9orf85,CAMK2D, CAPN7, CAPRIN2, CARD8, CARKD, CAST, CCDC25, CCDC90B, CCNDBP1,CCNL1, CD46, CD55, CD99P1, CDC14B, CDC16, CHD3, CHEK2, CHKB, CKLF,CLCN6, CNOT10, COL16A1, COL6A3, COPS7A, COQ6, COX20, CPEB2, CPT1C, CRAT,CRLS1, CRNDE, CRYZ, CSAD, CTDSPL, CUTC, CWC25, CYB561D2, CYP20A1, DBT,DCAF10, DCAF11, DCAF17, DDB2, DGKA, DHRSX, DIMT1, DIS3, DLG1, DMD,DMTF1, DNAJC2, DNM1L, DNMT1, DOCK7, DPY19L4, DRAM2, DSCR3, DTNBP1,DUSP11, DUSP22, DYNC2H1, EBPL, EDC3, EDRF1, EHBP1, EHMT2, EIF4A2,EIF4E2, ELK1, ELN, ELOVL1, ENOSF1, EPB41L1, ERBB2IP, ERLEC1, ERMAP,ETHE1, EVC, EVI5L, FAM104A, FAM111A, FAM134C, FAM149B1, FAM172A,FAM204A, FAM211A-AS1, FAP, FBXL12, FBXO25, FBXW11, FGF5, FHL2, FIP1L1,FLAD1, FLNA, FN1, FNIP2, FOXN3, FYN, GAB1, GABPB2, GABRE, GALNS, GFPT2,GIT2, GK, GLS, GOLGA4, GOLGB1, GOLTIB, GPR133, GPR180, GRIPAP1, GTF3A,GUF1, GUSB, HACL1, HAUS7, HCFC1R1, HDAC10, HDAC7, HECTD3, HERC3, HIPK3,HMGXB4, HNRNPD, HPS1, HUWE1, IFT88, IGF2BP2, ING4, IPO8, IRAK4, ISOC2,IST1, KDM4C, KIAA0100, KIF3A, KITLG, KLC1, LACC1, LAMTOR3, LAS1L, LENG8,LETMD1, LINC00963, LMAN2L, LMO7, LOXL3, LPHN2, LRRC28, LRRC32, LTA4H,LTBP1, LTBP3, LTBP4, LUC7L, LYPLAL1, LYRM7, LZTFL1, MACF1, MADD, MAN2C1,MAP3K3, MAP4K4, MAPK11, MAPK12, MBD5, MBOAT2, MED13, MED15, MEG3, MEGF6,METTL14, MFF, MFSD12, MGEA5, MGST2, MINK1, MIR22HG, MKS1, MLF1, MLH1,MLLT6, MLST8, MMP19, MORF4L2, MOSPD1, MPDZ, MPI, MPV17, MRPL33, MSRB3,MTCH2, MTMR2, MTMR3, MTMR6, MTRR, MTSS1L, MYBL1, MYCBP2, MYLK, MYNN,MYO19, MYO5A, NADK2, NAE1, NBN, NEK1, NEXN, NFE2L1, NIPA2, NLRC5, NLRX1,NPR2, NPRL3, NSFL1C, NSUN4, NT5C2, NUB1, NUP43, NUPL2, NUTM2A- AS1,OARD1, ODF2, ODF2L, OPTN, ORMDL1, OS9, PACRGL, PAM, PARD3, PARL, PARP11,PATL1, PCBP2, PCID2, PCM1, PCNXL2, PCNXL4, PCYT2, PDLIM2, PEAK1, PEX1,PEX11A, PEX5, PFDN1, PFDN6, PFKM, PHKG2, PI4KB, PIGG, PIGT, PIK3C2A,PIKFYVE, PILRB, PKIG, PLA2G12A, PLA2R1, PLAGL1, PLBD2, PMS2P3, PODNL1,POLR3GL, PPAP2A, PPFIBP1, PPIL3, PPIP5K2, PPM1M, PPP1R12A, PPP1R21,PPP2R3C, PPP4C, PPP6R2, PPRC1, PREB, PRKAG1, PRMT2, PRPF40B, PRR16,PRR4, PSME4, PTPN13, PTPN21, PTPN23, PTPN4, PTPRA, PVR, PXDN, R3HDM4,RAB1 1FIP2, RABEPK, RAD1, RALGPS2, RBCK1, RCOR3, REPS1, RGL2, RGN,RHBDD2, RHOBTB1, RHOT1, RIF1, RIPK2, RNF146, RNF170, RNF214, RNFT1,ROBO1, RP11- 1055B8.7, RP11-33B1.1, RP11-383H13.1, RP11-773D16.1,RP13-279N23.2, RPAIN, RPL7L1, RPP14, RPS6KB2, RSU1, RTEL1,RTEL1-TNFRSF6B, RUFY2, RWDD2B, RWDD4, SBF1, SCMH1, SEC31B, SECISBP2L,SEMA4F, SENP1, SENP6, SERAC1, SETD5, SFXN4, SGSM3, SHMT2, SIPA1L1,SLC22A17, SLC25A17, SLC25A32, SLC25A36, SLC35A1, SLC35D2, SLC37A3,SLC38A2, SLC38A6, SLC4A7, SLC5A6, SLC7A6, SLC9B2, SLIT2, SLMAP, SLMO1,SMAD5, SMARCD1, SMC5, SMEK2, SMPDL3A, SMURF2, SNAPC5, SNED1, SNHG14,SNHG15, SNRPA1, SNRPG, SNX14, SNX21, SPATA20, SPTAN1, ST7, STARD5,STAT6, STK16, STK19, STRA13, STRADA, STX16, STX16-NPEPL1, STX3, STXBP3,STYXL1, SUGT1, SULF1, SUN2, SUPT20H, TAF1, TANGO2, TARBP2, TAS2R14, TAZ,TBC1D14, TBC1D17, TBC1D25, TBC1D5, TBCK, TBX15, TCERG1, TEAD2, TEP1,TFDP1, TFDP2, TFP1, THAP6, THBS3, THOC2, TIMM21, TMCO4, TMEM11,TMEM120A, TMEM194A, TMEM260, TMEM39B, TMEM62, TMOD2, TMUB2, TMX3, TOM1,TP53INP1, TP53TG1, TPD52L2, TPRA1, TRAPPC12, TREX2, TRIO, TRIP10, TRPC1,TRPM4, TRPT1, TSEN15, TSR1, TSTD3, TUBG2, TULP3, TXNDC11, U2AF1L4, UACA,UBA7, UBE2A, UBE2D1, UBN2, UBQLN1, UFD1L, UNC5B, URGCP, USMG5, USP24,USP25, USP53, VAMP7, VCAN, WBP1, WDFY2, YEATS2, YIPF1, YME1L1, YY1AP1,ZBTB80S, ZCCHC6, ZCCHC8, ZDHHC16, ZDHHC7, ZFAND1, ZFAND5, ZFAS1, ZMIZ1,ZMYM4, ZMYM5, ZNF160, ZNF207, ZNF248, ZNF280D, ZNF384, ZNF512, ZNF720,and ZZZ3.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ IDNO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 6.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ IDNO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 6.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutated wildtype gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein themutated wildtype gene transcript comprises, three exons and two intronsoperably linked in the following order: Exon 1, Intron 1, Exon 2, Intron2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequenceselected from the group consisting of: CAAgtaagc (SEQ ID NO: 9),GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga(SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO:14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), andwherein the mutated wildtype gene transcript is transcribed from a geneselected from Table 6.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutated wildtype gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein themutated wildtype gene transcript comprises, three exons and two intronsoperably linked in the following order: Exon 1, Intron 1, Exon 2, Intron2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequenceselected from the group consisting of: CAAguaagc (SEQ ID NO: 17),GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga(SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO:22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), andwherein the mutated wildtype gene transcript is transcribed from a geneselected from Table 6.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), wherein N represents any DNA nucleotide, and whereinthe predicted wildtype gene transcript is transcribed from a geneselected from Table 6.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype gene transcript is transcribed from a gene selected from Table6.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype gene transcript istranscribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype gene transcript istranscribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected from:CACTAGgtgaga (SEQ ID NO: 3), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected from:CACUAGgugaga (SEQ ID NO: 7), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutated wildtype gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein themutated wildtype gene transcript comprises, three exons and two intronsoperably linked in the following order: Exon 1, Intron 1, Exon 2, Intron2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequenceselected from the group consisting of: CACTAGgtgagc (SEQ ID NO: 11), andCTGAAgtcagt (SEQ ID NO: 15), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutated wildtype gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein themutated wildtype gene transcript comprises, three exons and two intronsoperably linked in the following order: Exon 1, Intron 1, Exon 2, Intron2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, a sequenceselected from the group consisting of: CACUAGgugagc (SEQ ID NO: 19), andCUGAAgucagu (SEQ ID NO: 23), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell with Compound(I), and wherein the gene transcript is transcribed from a gene selectedfrom Table 6.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon inclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon exclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell in vivo or invitro with Compound (I), and wherein the gene transcript is transcribedfrom a gene selected from Table 6.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a wildtype gene transcript in a subject in need thereofcomprising, administering Compound (I) to the subject, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, wherein the subject ishuman, and wherein the gene is selected from Table 6.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a wildtype gene transcript in a subject in need thereofcomprising, administering Compound (I) to the subject, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, wherein one or more of themature RNA isoforms produce a functional protein, and wherein the geneis selected from Table 6.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell, andwherein the gene transcript is transcribed from a gene selected fromTable 6.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having a mutation in a gene transcript thereof isselected from Table 6.

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutated wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the mutated wildtype gene transcript comprises, three exonsand two introns operably linked in the following order: Exon 1, Intron1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAgtaagc(SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO:11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13),ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutated wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the mutated wildtype gene transcript comprises, three exonsand two introns operably linked in the following order: Exon 1, Intron1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAguaagc(SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO:19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21),AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), andAGUguaagua (SEQ ID NO: 24), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the predicted wildtype gene transcript includes a nucleotidesequence selected from the group consisting of: CTTAG (SEQ ID NO: 25),NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31),TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34),TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43),GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46),TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49),AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55),NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58),NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61),ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype gene transcriptis transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from: CACTAGgtgaga (SEQ ID NO: 3), and wherein thewildtype gene transcript is transcribed from a gene selected from Table6.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from: CACUAGgugaga (SEQ ID NO: 7), and wherein thewildtype gene transcript is transcribed from a gene selected from Table6.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutated wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the mutated wildtype gene transcript comprises, three exonsand two introns operably linked in the following order: Exon 1, Intron1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of:CACTAGgtgagc (SEQ ID NO: 11), and CTGAAgtcagt (SEQ ID NO: 15), andwherein the mutated wildtype gene transcript is transcribed from a geneselected from Table 6.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutated wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the mutated wildtype gene transcript comprises, three exonsand two introns operably linked in the following order: Exon 1, Intron1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of:CACUAGgugagc (SEQ ID NO: 19), and CUGAAgucagu (SEQ ID NO: 23), andwherein the mutated wildtype gene transcript is transcribed from a geneselected from Table 6.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell with Compound(I), wherein the gene transcript is transcribed from a gene selectedfrom Table 6.

Another aspect described herein is use of Compound (I) to increase exoninclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to increase exonexclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Table 6.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell in vivo or invitro with Compound (I), wherein the gene transcript is transcribed froma gene selected from Table 6.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a wildtype genetranscript in a subject in need thereof comprising, administeringCompound (I) to the subject, wherein exon inclusion or exon exclusion ismodulated in one or more mature RNA isoforms produced from the genetranscript, wherein the subject is human, and wherein the gene isselected from Table 6.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a wildtype genetranscript in a subject in need thereof comprising, administeringCompound (I) to the subject, wherein exon inclusion or exon exclusion ismodulated in one or more mature RNA isoforms produced from the genetranscript, wherein one or more of the mature RNA isoforms produce afunctional protein, and wherein the gene is selected from Table 6.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a wildtype genetranscript in a subject in need thereof comprising, administering to thesubject a pharmaceutical composition of Compound (I) and apharmaceutically acceptable carrier, excipient, or diluent, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, and wherein the gene isselected from Table 6.

Another aspect described herein is use of Compound (I), wherein a genehaving a mutation in a gene transcript thereof is selected from thegroup consisting of Table 6.

Methods of Modulating Mutated Gene Isoforms

One aspect described herein is Compound (I) for use in a method tomodulate the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Table 7.

Table 7 lists mutated genes predicted by SpliceAI scores and the CNNModel, as described herein, that may be modulated by Compound (I) towardexon inclusion.

TABLE 7 ABCA4, ABCC9, ACADSB, ADAM10, AGK, ALDH3A2, ALMS1, ANTXR2, APC,ARMC9, ASAH1, ASPM, ATM, ATRX, BBS4, BFSP1, BMPR2, BRCA1, BRCA2, CA5A,CAPN3, CD3D, CDH1, CDH23, CERKL, CFTR, CHD7, CLCN1, CLMP, CLN3, CNGB3,COG6, COL11A1, COL3A1, COL4A3, COL4A5, COL5A2, CSTB, CTNS, CTU2, CUBN,CWC27, CYBB, DCX, DGKE, DGUOK, DMD, DNAH5, DNAH9, DYNC2H1, DYNC2LI1,EBF3, EP300, F10, F13A1, FBN1, FUT8, G6PC, GAA, GABRG2, GCK, GLA, GNB5,GNPTAB, GPR143, GPX4, GRHPR, GRN, GUCY2C, GYPA, HBB, IDH1, IFT57,IL36RN, KDSR, KIAA0586, KIAA1109, KIF14, KIT, KMT2D, KRIT1, LAMB3, LDLR,LIPA, LMNA, MCFD2, MLH1, MMAB, MPC1, MSH2, MTM1, MYBPC3, MYO7A, NF1,NIPBL, NPHP1, NR3C2, NSD1, OCA2, OFD1, OGT, ORC6, OTC, OTOGL, PAFAH1B1,PAH, PARN, PDCD10, PIGN, PMS2, POLG, POMGNT1, PPT1, PRMT7, PTEN, RAD51B,RAD51C, RB1, RHAG, RNF216, RTTN, SCN1A, SLC10A7, SLC12A1, SLC4A11, SMS,SPAST, SPG11, SPTA1, SPTB, SRD5A2, STXBP1, SYNGAP1, TGFBR2, TJP2,TMEM138, TMPRSS6, TP53, TPO, TRAPPC2, TRIM37, TYR, UROD, VMA21, VPS13B,WDR35, WDR73, and XPC.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutated wildtype gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein thenon-mutated wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutated wildtype gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein thenon-mutated wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ IDNO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12),AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt(SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutantgene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ IDNO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20),AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu(SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutantgene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), wherein N represents any DNA nucleotide, and whereinthe predicted mutant gene transcript is transcribed from a gene selectedfrom Table 7.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedmutant gene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted mutant gene transcript istranscribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted mutant gene transcript istranscribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16),and wherein the mutant gene transcript is transcribed from a geneselected from Table 7.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24),and wherein the mutant gene transcript is transcribed from a geneselected from Table 7.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell with Compound(I), and wherein the gene transcript is transcribed from a gene selectedfrom Table 7.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon inclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon exclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 7.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell in vivo or invitro with Compound (I), and wherein the gene transcript is transcribedfrom a gene selected from Table 7.

Another aspect described herein a the use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof, wherein the method comprises,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein the subject is human, and wherein thegene is selected from Table 7.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein one or more of the mature RNA isoformsproduce a functional protein, and wherein the gene is selected fromTable 7.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell, andwherein the gene transcript is transcribed from a gene selected fromTable 7.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having a mutation in a gene transcript thereof isselected from Table 7.

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutated wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the non-mutated wildtype gene transcript comprises, threeexons and two introns operably linked in the following order: Exon 1,Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon2 comprises, a sequence selected from the group consisting of: CAAgtaagt(SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO:3), and CCAgtgagga (SEQ ID NO: 4), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutated wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the non-mutated wildtype gene transcript comprises, threeexons and two introns operably linked in the following order: Exon 1,Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon2 comprises, a sequence selected from the group consisting of: CAAguaagu(SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO:7), and CCAgugagga (SEQ ID NO: 8), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagc (SEQ ID NO:9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11),CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt(SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO:16), and wherein the mutant gene transcript is transcribed from a geneselected from Table 7.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagc (SEQ ID NO:17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19),CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu(SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO:24), and wherein the mutant gene transcript is transcribed from a geneselected from Table 7.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted mutantgene transcript in a cell comprising, contacting the cell with Compound(I), wherein the predicted mutant gene transcript includes a nucleotidesequence selected from the group consisting of: CTTAG (SEQ ID NO: 25),NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31),TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34),TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43),GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46),TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49),AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55),NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58),NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61),ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted mutant gene transcript istranscribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: AGCCAAgtatgt (SEQ ID NO:13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript istranscribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: AGCCAAguaugu (SEQ ID NO:21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), andAGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript istranscribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell with Compound(I), wherein the gene transcript is transcribed from a gene selectedfrom Table 7.

Another aspect described herein is use of Compound (I) to increase exoninclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to increase exonexclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Table 7.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell in vivo or invitro with Compound (I), wherein the gene transcript is transcribed froma gene selected from Table 7.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript,wherein the subject is human, and wherein the gene is selected fromTable 7.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript,wherein one or more of the mature RNA isoforms produce a functionalprotein, and wherein the gene is selected from Table 7.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, modulating the production ofone or more mature RNA isoforms from a gene transcript by administeringto the subject a pharmaceutical composition of Compound (I) and apharmaceutically acceptable carrier, excipient, or diluent, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, and wherein the gene isselected from Table 7.

Another aspect described herein is use of Compound (I), wherein a genehaving a mutation in a gene transcript thereof is selected from thegroup consisting of Table 7.

One aspect described herein is Compound (I) for use in a method tomodulate the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Table 8.

Table 8 lists mutated genes predicted by SpliceAI scores and the CNNModel, as described herein, that may be modulated by Compound (I) towardexon exclusion.

TABLE 8 BRCA1, BRIP1, CDAN1, CLN3, COL6A1, COL7A1, CTSK, EBP, ERCC6, F8,FBN1, FIG4, FLT3, GLA, HFE, LHCGR, MAPT, OTC, SCN5A, SDCCAG8, SDHD,SNX10, STK11, TCIRG1, TECTA, TFR2, and TP53.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutated wildtype gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein thenon-mutated wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutated wildtype gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein thenon-mutated wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ IDNO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12),AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt(SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutantgene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ IDNO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20),AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu(SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutantgene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), wherein N represents any DNA nucleotide, and whereinthe predicted mutant gene transcript is transcribed from a gene selectedfrom Table 8.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedmutant gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted mutant gene transcript istranscribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted mutant gene transcript istranscribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected from:AGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript istranscribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected from:AGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript istranscribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell with Compound(I), and wherein the gene transcript is transcribed from a gene selectedfrom Table 8.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon inclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon exclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell in vivo or invitro with Compound (I), and wherein the gene transcript is transcribedfrom a gene selected from Table 8.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein the subject is human, and wherein thegene is selected from Table 8.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein one or more of the mature RNA isoformsproduce a functional protein, and wherein the gene is selected fromTable 8.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell, andwherein the gene transcript is transcribed from a gene selected fromTable 8.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having a mutation in a gene transcript thereof isselected from Table 8.

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutated wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the non-mutated wildtype gene transcript comprises, threeexons and two introns operably linked in the following order: Exon 1,Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon2 comprises, a sequence selected from the group consisting of: CAAgtaagt(SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO:3), and CCAgtgagga (SEQ ID NO: 4), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutated wildtypegene transcript in a cell comprising, contacting the cell with Compound(I), wherein the non-mutated wildtype gene transcript comprises, threeexons and two introns operably linked in the following order: Exon 1,Intron 1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon2 comprises, a sequence selected from the group consisting of: CAAguaagu(SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO:7), and CCAgugagga (SEQ ID NO: 8), and wherein the mutated wildtype genetranscript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagc (SEQ ID NO:9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11),CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt(SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO:16), and wherein the mutant gene transcript is transcribed from a geneselected from Table 8.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagc (SEQ ID NO:17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19),CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu(SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO:24), and wherein the mutant gene transcript is transcribed from a geneselected from Table 8.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted mutantgene transcript in a cell comprising, contacting the cell with Compound(I), wherein the predicted mutant gene transcript includes a nucleotidesequence selected from the group consisting of: CTTAG (SEQ ID NO: 25),NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31),TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34),TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43),GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46),TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49),AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55),NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58),NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61),ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted mutant gene transcript istranscribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from: AGTgtaagta (SEQ ID NO: 16), and wherein themutant gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from: AGUguaagua (SEQ ID NO: 24), and wherein themutant gene transcript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell with Compound(I), wherein the gene transcript is transcribed from a gene selectedfrom Table 8.

Another aspect described herein is use of Compound (I) to increase exoninclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to increase exonexclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell in vivo or invitro with Compound (I), wherein the gene transcript is transcribed froma gene selected from Table 8.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript,wherein the subject is human, and wherein the gene is selected fromTable 8.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript,wherein one or more of the mature RNA isoforms produce a functionalprotein, and wherein the gene is selected from Table 8.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, modulating the production ofone or more mature RNA isoforms from a gene transcript by administeringto the subject a pharmaceutical composition of Compound (I) and apharmaceutically acceptable carrier, excipient, or diluent, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, and wherein the gene isselected from Table 8.

Another aspect described herein is use of Compound (I), wherein a genehaving a mutation in a gene transcript thereof is selected from thegroup consisting of Table 8.

Methods of Modulating Wildtype and Mutated Gene Isoforms

One aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), wherein the gene transcript comprises, three exonsand two introns operably linked in the following order: Exon 1, Intron1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAgtaagt(SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO:3), and CCAgtgagga (SEQ ID NO: 4), and wherein the gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), wherein the gene transcript comprises, three exonsand two introns operably linked in the following order: Exon 1, Intron1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAguaagu(SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO:7), and CCAgugagga (SEQ ID NO: 8), and wherein the gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), wherein the gene transcript comprises, three exonsand two introns operably linked in the following order: Exon 1, Intron1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAgtaagc(SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO:11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13),ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16), and wherein the gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), wherein the gene transcript comprises, three exonsand two introns operably linked in the following order: Exon 1, Intron1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAguaagc(SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO:19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21),AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), andAGUguaagua (SEQ ID NO: 24), and wherein the gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), wherein N represents any DNA nucleotide, and whereinthe predicted gene transcript is transcribed from a gene selected fromTables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in a method formodulating exon inclusion or exon exclusion in one or more mature RNAisoforms from a gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), and wherein the gene transcriptis transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or8.

Another aspect described herein is Compound (I) for use in a method forincreasing exon inclusion in one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in a method forincreasing exon exclusion in one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in a method formodulating exon inclusion or exon exclusion in one or more mature RNAisoforms from a gene transcript in a cell, wherein the method comprises,contacting the cell in vivo or in vitro with Compound (I), and whereinthe gene transcript is transcribed from a gene selected from Tables 1,2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein the subject is human, and wherein thegene transcript is transcribed from a gene selected from Tables 1, 2, 3,4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein one or more of the mature RNA isoformsproduce a functional protein, and wherein the gene is selected fromTables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell, andwherein the gene transcript is transcribed from a gene selected fromTables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having the mutated transcript is selected from Tables 1,2, 3, 4, 5, 6, 7 or 8.

One aspect described herein is a method for modulating the production ofone or more mature RNA isoforms from a gene transcript in a cellcomprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7 or 8.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ IDNO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), andwherein the gene transcript is transcribed from a gene selected fromTables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ IDNO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), andwherein the gene transcript is transcribed from a gene selected fromTables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ IDNO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12),AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt(SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7 or 8.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ IDNO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20),AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu(SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7 or 8.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a predicted genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the predicted gene transcript includes a nucleotide sequenceselected from the group consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ IDNO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO:32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO:35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO:38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO:41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO:44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO:47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO:50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO:53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO:56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO:59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO:62), and CTGTA (SEQ ID NO: 63), wherein N represents any DNA nucleotide,and wherein the predicted gene transcript is transcribed from a geneselected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a predicted genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the predicted gene transcript includes a nucleotide sequenceselected from the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ IDNO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO:34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO:39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO:43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO:47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO:51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO:55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO:58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO:63), wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a predicted genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the predicted gene transcript includes a nucleotide sequenceselected from the group consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ IDNO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO:72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO:75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO:78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO:83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO:86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO:89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO:92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO:96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO:100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein Nrepresents any RNA nucleotide, and wherein the predicted wildtype ormutant gene transcript is transcribed from a gene selected from Tables1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a predicted genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the predicted gene transcript includes a nucleotide sequenceselected from the group consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ IDNO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO:73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO:78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO:85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO:88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO:93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO:98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein Nrepresents any RNA nucleotide, and wherein the predicted wildtype ormutant gene transcript is transcribed from a gene selected from Tables1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for modulating exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell with Compound(I), wherein the gene transcript is transcribed from a gene selectedfrom Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for increasing exoninclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7 or 8.

Another aspect described herein is a method for increasing exonexclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7 or 8.

Another aspect described herein is a method for modulating exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell in vivo or invitro with Compound (I), wherein the gene transcript is transcribed froma gene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof comprising, administering Compound (I) to thesubject, wherein exon inclusion or exon exclusion is modulated in one ormore mature RNA isoforms produced from the gene transcript, wherein thesubject is human, and wherein the gene transcript is transcribed from agene selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof comprising, administering Compound (I) to thesubject, wherein exon inclusion or exon exclusion is modulated in one ormore mature RNA isoforms produced from the gene transcript, wherein oneor more of the mature RNA isoforms produce a functional protein, andwherein the gene is selected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is a method for treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof comprising, modulating the production of one ormore mature RNA isoforms from a gene transcript by administering to thesubject a pharmaceutical composition of Compound (I) and apharmaceutically acceptable carrier, excipient, or diluent, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, and wherein the gene isselected from Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Another aspect described herein is use of Compound (I), wherein a genehaving a mutation in a gene transcript thereof is selected from thegroup consisting of Tables 1, 2, 3, 4, 5, 6, 7 or 8.

Methods of Modulating Wildtype Gene Isoforms

One aspect described herein is Compound (I) for use in a method tomodulate the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Table 9.

Table 9 lists wildtype genes identified by RNA sequencing, as describedherein, that may be unchanged by Compound (I) toward either or both exoninclusion and exon exclusion.

TABLE 9 AAMDC, ABCA2, ABCC3, ABCD4, ABHD16A, ABI3BP, ACAD10, ACAP3,ACCS, ACOT9, ACTN1, ADAM15, AFTPH, AK4, AMBRA1, AMDHD2, AMIGO2, AMOTL1,AMZ2P1, ANAPC11, ANKRD17, ANO6, AOX1, ARHGEF10, ARID5A, ARIH2, ARMC10,ARSJ, ASCC2, ATG12, ATG13, ATG4B, ATP5C1, ATP6C, B3GALNT1, BAZ2A,BCL2L2, BEND6, BIRC6, BLOC1S6, BRD8, BTBD3, BTF3L4, C10orf118, C11orf30,C11orf57, C14orf159, C2orf76, C9orf156, CACNA1C, CAMK2G, CAMSAP1,CAPN10, CARF, CCDC126, CCDC136, CCDC25, CCNL2, CCNT1, CCNYL1, CD27-AS1,CDC42BPA, CDCA7L, CDK5RAP2, CEP164, CIRBP, CLASP2, CPNE1, CSDE1,CSNK1A1, CTIF, CTSB, DCAF8, DCTD, DGUOK, DLGAP1-AS1, DMKN, DMWD, DNAAF2,DNAJC14, DNAJC24, DPH7, DPM1, DUS2, ECHDC2, EHBP1L1, EIF4G2, ELMOD3,EMC4, ENC1, EP400, EPS15L1, ERMARD, EVA1A, FAM114A1, FAM13B, FAM160B2,FAM173A, FAM175A, FAM208B, FAM35A, FAM45A, FDPS, FGFR1, FHOD3, FLNB,FNBP1, FOSL1, FOXRED2, FRS2, GAS7, GBP3, GEMIN8, GLIS3, GLRB, GLT8D1,GNAS, GPATCH8, GPBP1, GRB10, HDAC9, HMCN1, HNRNPK, HSCB, IL17RA, IL17RC,IL6, INTS9, IP6K2, KANSL3, KAT6A, KCTD20, KIAA0232, KIAA0368, KIAA0753,KIAA1551, KIAA1586, KIAA1731, KIFC3, KLHL12, KTN1, LBR, LDB2, LRP12,MADD, MAP2K5, MAP7D1, MAPK9, MAZ, MBD1, MCCC2, MECR, MED23, MEGF6,MEIS1, METTL10, METTL21A, MGLL, MICU3, MKNK2, MLLT10, MPPE1, MRI1,MRPL55, MTIF2, MXI1, MXRA7, MYCBP2, MYO18A, MYO5A, N6AMT2, NCK2, NCOR2,NEDD1, NIN, NPRL3, NTMT1, NTPCR, NUBP2, NUMB, NUP98, NUTF2, OPN3, OSER1-AS1, P4HA2, PARD3, PCNXL2, PDGFC, PDP1, PDPR, PDXDC2P, PEAK1, PFDN5,PHLPP2, PIGF, PIGP, PIGQ, PINX1, PLD3, PLSCR4, PPP1R18, PPP6R3, PRDM5,PRRC2B, PRUNE, PTAR1, PTPRG, PTPRS, PUF60, PUM2, R3HDM1, RAD51D, RAF1,RAPH1, RBM10, RBM27, RBM4, RBM5, RCC1, RFC2, RGL1, RIF1, RILP, RILPL2,RNF14, RNF8, RNGTT, RP11-705C15.2, RP1-178F15.4, RPAIN, RPP38, RPS24,RPUSD1, RRNAD1, RTN2, RUNX1, SCRN3, SEC13, SEC31A, SETD2, SEZ6L2, SGSM2,SIKE1, SLAIN2, SLC30A6, SLC38A9, SLC39A9, SLFN11, SLMAP, SLTM, SMEK2,SMG7, SMURF2, SNHG14, SPEN, SPIDR, SRSF2, STAG1, STAG2, STARD3, STARD4,STK38L, STOML1, STXBP5, SUOX, SYNE1, SYNJ2BP, TAMM41, TBC1D32, TBCE,TBCEL, TCF20, TCF7L2, TENM2, TET2, TFB2M, TFDP2, TGIF1, THADA, THTPA,THTPA, TJAP1, TJP1, TLK2, TMEM119, TMEM161B, TMEM175, TMEM230, TMUB2,TOR1AIP2, TOR3A, TP53BP2, TRA2A, TRIM37, TRMU, TROVE2, TSPAN5, TULP3,U2AF1, UCHL5, UPF3A, UPP1, USP3, VDR, VEGFA, VIPAS39, VPS13D, WARS,WDR27, WHSC1, WNK1, XIAP, XPNPEP3, YTHDF2, YWHAB, ZBTB38, ZCCHC6, ZEB1,ZFAT, ZFX, ZMYM1, ZNF140, ZNF217, ZNF260, ZNF266, ZNF3, ZNF346, ZNF37A,ZNF419, ZNF426, ZNF529, ZNF585B, ZNF638, ZNF655, ZNF75A, ZNF767, andZSCAN32.

Another aspect described herein is Compound (I) for use in a method tomodulate the production of one or more mature RNA isoforms from awildtype gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the wildtype genetranscript is transcribed from a gene other than a gene selected fromTable 9.

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene selected from Table 9.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript is transcribed from a gene otherthan a gene selected from Table 9.

One aspect described herein is Compound (I) for use in a method, whereinCompound (I) modulates the production of one or more mature RNA isoformsfrom a gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), and wherein the gene transcriptis transcribed from a gene selected from Table 9a.

Table 9a lists wildtype genes identified by RNA sequencing and mutatedgenes predicted by SpliceAI scores and the CNN model, as describedherein, which may be modulated by Compound (I) toward either or bothexon inclusion or exon exclusion and toward remaining unchanged.

TABLE 9a ABCC3, ABI3BP, ACAD10, ACTN1, ANO6, ARHGEF10, ARIH2, ASCC2,B3GALNT1, BIRC6, BLOC1S6, BRD8, C11orf30, C9orf156, CCDC25, DCAF8,DGUOK, ENC1, IP6K2, KTN1, MADD, MEGF6, MYO18A, MYO5A, NPRL3, PARD3,PCNXL2, PEAK1, PRUNE, RIF1, RPAIN, SLMAP, SLTM, SMEK2, SMURF2, SNHG14,TFDP2, TMUB2, TRIM37, TROVE2, TULP3, and ZCCHC6.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of: CAAgtaagc (SEQ ID NO:9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11),CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt(SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO:16), and wherein the mutant gene transcript is transcribed from a geneselected from Table 9a.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of: CAAguaagc (SEQ ID NO:17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19),CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu(SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO:24), and wherein the mutant gene transcript is transcribed from a geneselected from Table 9a.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), wherein N represents any DNA nucleotide, and whereinthe predicted wildtype or mutant gene transcript is transcribed from agene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Table 9a.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the method, wherein Compound (I)modulates exon inclusion or exon exclusion to produce one or more matureRNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon inclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon exclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell in vivo or invitro with Compound (I), and wherein the gene transcript is transcribedfrom a gene selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein the subject is human, and wherein thegene is selected from Table 9a.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein one or more of the mature RNA isoformsproduce a functional protein, and wherein the gene is selected fromTable 9a.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell, andwherein the gene transcript is transcribed from a gene selected fromTable 9a.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having a mutation in a gene transcript thereof isselected from Table 9a.

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype genetranscript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype genetranscript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc(SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO:13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript istranscribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc(SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO:21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), andAGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript istranscribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27),CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30),TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33),TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36),TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39),GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42),AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51),TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54),GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57),CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60),AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Table 9a.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell with Compound(I), wherein the gene transcript is transcribed from a gene selectedfrom Table 9a.

Another aspect described herein is use of Compound (I) to increase exoninclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to increase exonexclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell in vivo or invitro with Compound (I), wherein the gene transcript is transcribed froma gene selected from Table 9a.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript,wherein the subject is human, and wherein the gene is selected fromTable 9a.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript,wherein one or more of the mature RNA isoforms produce a functionalprotein, and wherein the gene is selected from Table 9a.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering to the subject apharmaceutical composition of Compound (I) and a pharmaceuticallyacceptable carrier, excipient, or diluent, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, and wherein the gene is selected from Table9a.

Another aspect described herein is use of Compound (I), wherein a genehaving a mutation in a gene transcript thereof is selected from thegroup consisting of Table 9a.

One aspect described herein is Compound (I) for use in a method tomodulate the production of one or more mature RNA isoforms from awildtype gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the wildtype genetranscript is transcribed from a gene selected from Table 10.

Table 10 lists wildtype genes identified by RNA sequencing, modulated bykinetin toward either or both exon inclusion and exon exclusion⁹³.

TABLE 10 ANKRD10, BRD8, C2CD5, CAPRIN2, CHD3, CRYZ, CYLD, DUSP11, EDEM2,HSD17B4, IKBKAP, KIF3A, KLC1, L3HYPDH, LETMD1, MORF4L2, NABP1, NEK1,NEXN, PLA2G12A, PPFIBP1, PPIP5K2, RHOT1, RPL7L1, RUFY2, SBF1, SDCCAG8,SECISBP2L, SLC4A7, SNX14, STARD4, STX16, SUCO, SUPT20H, TEAD2, TEP1,TIA1, ZFAND1, and ZNF207.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ IDNO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 10.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ IDNO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 10.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ IDNO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12),AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt(SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutantgene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ IDNO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20),AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu(SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutantgene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), wherein N represents any DNA nucleotide, and whereinthe predicted wildtype or mutant gene transcript is transcribed from agene selected from Table 10.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Table 10.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 10.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 10.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected from:CAAgtaagt (SEQ ID NO: 1), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 10.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected from:CAAguaagu (SEQ ID NO: 5), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 10.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), and wherein the gene transcriptis transcribed from a gene other than a gene selected from Table 10.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell, andwherein the gene transcript is transcribed from a gene selected fromTable 10.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having a mutation in a gene transcript thereof isselected from the group consisting of Table 10.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having a mutation in a gene transcript thereof is a geneother than the gene selected from the group consisting of Table 10.

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 10.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 10.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 10.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagc (SEQ ID NO:9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11),CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt(SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO:16), and wherein the mutant gene transcript is transcribed from a geneselected from Table 10.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagc (SEQ ID NO:17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19),CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu(SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO:24), and wherein the mutant gene transcript is transcribed from a geneselected from Table 10.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27),CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30),TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33),TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36),TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39),GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42),AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51),TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54),GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57),CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60),AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Table 10.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 10.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 10.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 10.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from: CAAgtaagt (SEQ ID NO: 1), and wherein thewildtype gene transcript is transcribed from a gene selected from Table10.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from: CAAguaagu (SEQ ID NO: 5), and wherein thewildtype gene transcript is transcribed from a gene selected from Table10.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene selected from Table 10.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene other than a gene selectedfrom Table 10.

One aspect described herein is Compound (I) for use in a method tomodulate the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), wherein the gene transcript is transcribed from agene selected from Table 11.

Table 11 lists wildtype genes identified by RNA sequencing, modulated bykinetin toward exon inclusion⁹³.

TABLE 11 CYLD, EDEM2, HSD17B4, IKBKAP, KLC1, L3HYPDH, NABP1, SDCCAG8,SUCO, SUPT20H, TIA1, and ZNF207.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ IDNO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 11.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ IDNO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 11.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ IDNO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12),AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt(SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutantgene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ IDNO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20),AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu(SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutantgene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), wherein N represents any DNA nucleotide, and whereinthe predicted wildtype or mutant gene transcript is transcribed from agene selected from Table 11.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Table 11.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 11.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 11.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected from:CAAgtaagt (SEQ ID NO: 1), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 11.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected from:CAAguaagu (SEQ ID NO: 5), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 11.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), and wherein the gene transcriptis transcribed from a gene selected from Table 11.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), and wherein the gene transcriptis transcribed from a gene other than a gene selected from Table 11.

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene selected from Table 11.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 11.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 11.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagc (SEQ ID NO:9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11),CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt(SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO:16), and wherein the mutant gene transcript is transcribed from a geneselected from Table 11.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagc (SEQ ID NO:17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19),CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu(SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO:24), and wherein the mutant gene transcript is transcribed from a geneselected from Table 11.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27),CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30),TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33),TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36),TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39),GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42),AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51),TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54),GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57),CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60),AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Table 11.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 11.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 11.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 11.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from: CAAgtaagt (SEQ ID NO: 1), and wherein thewildtype gene transcript is transcribed from a gene selected from Table11.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from: CAAguaagu (SEQ ID NO: 5), and wherein thewildtype gene transcript is transcribed from a gene selected from Table11.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene other than a gene selectedfrom Table 11.

One aspect described herein is Compound (I) for use in a method tomodulate the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Table 12.

Table 12 lists wildtype genes identified by RNA sequencing, modulated bykinetin toward exon exclusion⁹³.

TABLE 12 ANKRD10, BRD8, C2CD5, CAPRIN2, CHD3, CRYZ, DUSP11, KIF3A,LETMD1, MORF4L2, NEK1, NEXN, PLA2G12A, PPFIBP1, PPIP5K2, RHOT1, RPL7L1,RUFY2, SBF1, SECISBP2L, SLC4A7, SNX14, STARD4, STX16, SUPT20H, TEAD2,TEP1, ZFAND1, and ZNF207.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: aspect described herein is Compound (I) for use inthe method, wherein Compound (I) modulates the production of one or moremature RNA isoforms from a wildtype gene transcript in a cell, whereinthe method comprises, contacting the cell with Compound (I), wherein thewildtype gene transcript comprises, three exons and two introns operablylinked in the following order: Exon 1, Intron 1, Exon 2, Intron 2, andExon 3, wherein a 5′ splice site of Exon 2 comprises, a sequence otherthan a sequence selected from the group consisting of: CAAgtaagt (SEQ IDNO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 12.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 12.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of: CAAgtaagc (SEQ ID NO:9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11),CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt(SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO:16), and wherein the mutant gene transcript is transcribed from a geneselected from Table 12.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of: CAAguaagc (SEQ ID NO:17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19),CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu(SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO:24), and wherein the mutant gene transcript is transcribed from a geneselected from Table 12.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), wherein N represents any DNA nucleotide, and whereinthe predicted wildtype or mutant gene transcript is transcribed from agene selected from Table 12.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Table 12.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 12.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 12.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), and wherein the gene transcriptis transcribed from a gene other than a gene selected from Table 12.

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene selected from Table 12.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype genetranscript is transcribed from a gene selected from Table 12.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype genetranscript is transcribed from a gene selected from Table 12.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc(SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO:13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript istranscribed from a gene selected from Table 12.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc(SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO:21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), andAGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript istranscribed from a gene selected from Table 12.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27),CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30),TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33),TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36),TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39),GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42),AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51),TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54),GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57),CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60),AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Table 12.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 12.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 12.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 12.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene other than a gene selectedfrom Table 12.

One aspect described herein is Compound (I) for use in a method tomodulate the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Table 13.

Table 13 lists wildtype genes identified by RNA sequencing, as describedin International Application No. PCT/US2016/013553, filed on Jan. 15,2016, and published as International Publication No. WO2016/115434 onJul. 21, 2016, the entire contents which are incorporated herein byreference, that may be modulated by Compound (I) toward exon inclusion.

TABLE 13 ABI2, ARFGEF2, ARHGEF6, BMP2K, C19orf12, CACNA1S, CC2D2A,CDKL5, CHD2, CHD7, CHD8, CHRNA4, COL6A3, CUL4B, DEPDC5, DES, DMD,DNAJC6, DYNC2H1, FBN1, FIG4, FKTN, FMR1, GOSR2, GRIN2A, HDAC8, IGHMBP2,IKBKAP, KDM5C, LAMA2, LRRK2, LRSAM1, MBD5, MECP2, MICU1, MTM1, NEB,OPHN1, PGAP1, PLEC, RB1, RYR1, SBF2, SCN1A, SCN9A, SLC35A3, SLC6A8,SLC9A9, SMCHD1, STXBP1, SYNGAP1, SZT2, TSC1, TSC2, and WDR45.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ IDNO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ IDNO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ IDNO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12),AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt(SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutantgene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ IDNO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20),AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu(SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutantgene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), wherein N represents any DNA nucleotide, and whereinthe predicted wildtype or mutant gene transcript is transcribed from agene selected from Table 13.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Table 13.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 13.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected from:CAAgtaagt (SEQ ID NO: 1), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected from:CAAguaagu (SEQ ID NO: 5), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), and wherein the gene transcriptis transcribed from a gene other than a gene selected from Table 13.

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene selected from Table 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagc (SEQ ID NO:9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11),CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt(SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO:16), and wherein the mutant gene transcript is transcribed from a geneselected from Table 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagc (SEQ ID NO:17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19),CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu(SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO:24), and wherein the mutant gene transcript is transcribed from a geneselected from Table 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27),CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30),TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33),TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36),TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39),GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42),AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51),TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54),GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57),CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60),AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Table 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from: CAAgtaagt (SEQ ID NO: 1), and wherein thewildtype gene transcript is transcribed from a gene selected from Table13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from: CAAguaagu (SEQ ID NO: 5), and wherein thewildtype gene transcript is transcribed from a gene selected from Table13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene other than a gene selectedfrom Table 13.

Preparation of Compound (I)

The small molecule splicing modulator compound described herein asCompound (I) has been disclosed in International Publication No.WO2016/115434 as Compound 100. Compound (I) can be prepared using themethods provided in International Publication WO2016/155434 and asdescribed herein.

Preparation of Compound (I)(2-chloro-N-(4-pyridylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine)

In brief, 4-(aminomethyl)pyridine (2, 3420 mg, 3.20 mL, 31.6 mmol, 1.19eq.) was added to a stirred suspension of2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (5001 mg, 26.60 mmol, 1.000eq.) (obtained from AstaTech Inc., Bristol, Pa.) in 1,4-dioxane (50.0mL) followed by addition of N,N-diisopropylethylamine (4450 mg, 6.00 mL,34.1 mmol, 1.28 eq.) at room temperature. The reaction mixture was thenheated to 90° C. and stirred at 90° C. overnight.

The reaction progress was monitored by LC-MS analysis of an aliquot ofthe reaction mixture. After about 12 h, approximately 6% of startingmaterial was detected by LC-MS. The reaction was quenched by waterresulting in an emulsion. The mixture was filtered through Celite andwashed with EtOAc (3×80 mL). The organic phase was separated and theaqueous phase was extracted with EtOAc (3×40 mL). The combined organicphases were washed with brine (50 mL) and then dried over sodium sulfate

The volatiles were removed under reduced pressure to produce a crudeproduct as a dark brown solid. EtOAc (100 mL) was added to the crudesolid and the mixture was heated at reflux for 15 min before slowlycooled to room temperature. The resulting precipitate was collected byfiltration, washed with cold EtOAc (30 mL) and diethyl ether (100 mL).The solid was dried under high vacuum overnight to produce2-chloro-N-(4-pyridylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine(Compound (I) as a light brown solid (3450 mg, 13.3 mmol, 50% yield.)

LC-MS: 0.63 min (254 nm), m/z 260.3, 262.3 [M+H]⁺, 258.2, 260.2 [M−H]⁻;¹H NMR (DMSO-d₆) δ: 11.65-11.85 (m, 1H), 8.51 (d, J=6.0 Hz, 2H),8.45-8.50 (m, 1H), 7.28-7.40 (m, 2H), 7.09-7.21 (m, 1H), 6.53-6.74 (m,1H), 4.61-4.81 (m, 2H).

As used herein, Compound (I) may have a form selected from the groupconsisting of a free acid, free base, prodrug, salt, hydrate, solvate,clathrate, isotopologue, racemate, enantiomer, diastereomer,stereoisomer, polymorph and tautomer form thereof.

In certain aspects described herein, the form of Compound (I) is a freeacid, free base or salt form thereof.

In certain aspects described herein, Compound (I) is a salt form.

In certain aspects described herein, the salt form of Compound (I) is apharmaceutically acceptable salt.

In certain aspects described herein, Compound (I) is isolated for use.

The term “pharmaceutically acceptable salt(s)”, as used herein, means asalt of Compound (I) that is safe and effective (i.e., non-toxic,physiologically acceptable) for use in mammals and possesses biologicalactivity, although other salts may be found useful. A salt of Compound(I) may be formed, for example, by reacting Compound (I) with an amountof acid or base, such as an equivalent amount, in a medium such as onein which the salt precipitates or in an aqueous medium followed bylyophilization.

Pharmaceutically acceptable salts include one or more salts of acidic orbasic groups present in compounds described herein. In certain aspects,acid addition salts may include, and are not limited to, acetate,ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate,bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate,ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate,glutamate, hydrochloride, iodide, isonicotinate, lactate, maleate,methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate,pantothenate, phosphate, propionate, saccharate, salicylate, succinate,sulfate, tartrate, thiocyanate, toluenesulfonate (also known astosylate), trifluoroacetate and the like. Certain aspects of acidaddition salts may further include acetate, bromide, chloride,dichloride, trichloride, hydrochloride, dihydrochloride, formate ortrifluoroacetate salts.

All such acid salts and base salts are intended to be included withinthe scope of pharmaceutically acceptable salts as described herein. Inaddition, all such acid and base salts are considered equivalent to thefree forms of Compound (I).

The use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like,is intended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or isotopologues of the instant compounds.

Another aspect, described herein includes Compound (I) selected from apolymorphic crystalline and amorphous form of Compound (I) and a salt,solvate, hydrate or ester of Compound (I).

Nomenclature for Compound (I) may differ slightly from other chemicalnames known to those skilled in the art; however, such differences willbe recognized by one skilled in the art as equivalents for the structureof Compound (I) provided herein.

Terminology

As used herein, the singular forms “a,” “an,” and “the,” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise.

The phrase “and/or,” as used herein and in the claims, is understood tomean “either or both” of the elements so conjoined, i.e., elements thatare conjunctively present in some cases and disjunctively present inother cases. Thus, as a non-limiting example, a reference to “A and/orB,” when used in conjunction with open-ended language such as“comprising” can refer, in one aspect, to A only (optionally includingelements other than B); in another aspect, to B only (optionallyincluding elements other than A); in yet another aspect, to both A and B(optionally including other elements); etc

As used herein and in the claims, the phrase “at least one,” inreference to a list of one or more elements, should be understood tomean at least one element selected from any one or more of the elementsin the list of elements, but not necessarily including at least one ofeach and every element specifically listed within the list of elements,and not excluding any combinations of elements in the list of elements.This definition also allows that elements may optionally be presentother than the elements specifically identified within the list ofelements to which the phrase “at least one” refers, whether related orunrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one aspect, to at least one, optionally including more thanone, A, with no B present (and optionally including elements other thanB); in another aspect, to at least one, optionally including more thanone, B, with no A present (and optionally including elements other thanA); in yet another aspect, to at least one, optionally including morethan one, A, and at least one, optionally including more than one, B(and optionally including other elements); etc.

When the term “about” is used in conjunction with a numerical range, itmodifies that range by extending the boundaries above and below thosenumerical values. In general, the term “about” is used herein to modifya numerical value above and below the stated value by a variance of 20%,10%, 5%, or 1%. In certain aspects, the term “about” is used to modify anumerical value above and below the stated value by a variance of 10%.In certain aspects, the term “about” is used to modify a numerical valueabove and below the stated value by a variance of 5%. In certainaspects, the term “about” is used to modify a numerical value above andbelow the stated value by a variance of 1%.

As used herein, the term “substantial change” in the context of theamount of one or more RNA transcripts, an alternative splice variantthereof or an isoform thereof, or one or more proteins thereof, eachexpressed as the product of one or more of genes, means that the amountof such products changes by a statistically significant amount such as,in a nonlimiting example, a p value less than a value selected from 0.1,0.01, 0.001, or 0.0001.

As used herein, the terms “subject” and “patient” are usedinterchangeably to refer to an animal or any living organism havingsensation and the power of voluntary movement, and which requires forits existence oxygen and organic food. Non-limiting examples includemembers of the human, equine, porcine, bovine, rattus, murine, canineand feline species. In some aspects, the subject is a mammal or awarm-blooded vertebrate animal. In certain aspects, the subject is anon-human animal. In specific aspects, the subject is a human.

When a range of values is listed herein, it is intended to encompasseach value and sub-range within that range. For example, “1-5 ng” or arange of “1 ng to 5 ng” is intended to encompass 1 ng, 2 ng, 3 ng, 4 ng,5 ng, 1-2 ng, 1-3 ng, 1-4 ng, 1-5 ng, 2-3 ng, 2-4 ng, 2-5 ng, 3-4 ng,3-5 ng, and 4-5 ng.

It will be further understood that the terms “comprises,” “comprising,”“includes,” and/or “including,” when used herein, specify the presenceof stated features, integers, steps, operations, elements, and/orcomponents, but do not preclude the presence or addition of one or moreother features, integers, steps, operations, elements, components,and/or groups thereof.

As used herein, the terms “treat,” “treatment,” “treating” refer totherapeutic treatments, wherein the object is to reverse, alleviate,ameliorate, inhibit, slow down or stop the progression or severity of adisorder. The term “treating” includes reducing or alleviating at leastone adverse effect or symptom of a condition, disease or disorder.Treatment is generally “effective” if one or more symptoms or clinicalmarkers are reduced. Alternatively, treatment is “effective” if theprogression of a disorder is reduced or halted. That is, “treatment”includes not just the improvement of symptoms or markers, but also acessation of, or at least slowing of, progress or worsening of symptomscompared to what would be expected in the absence of treatment.Beneficial or desired clinical results include, but are not limited to,alleviation of one or more symptom(s), diminishment of extent ofdisease, stabilized (i.e., not worsening) state of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, remission (whether partial or total), and/or decreasedmortality, whether detectable or undetectable. The term “treatment” of adisease also includes providing relief from the symptoms or side-effectsof the disease (including palliative treatment).

As used herein, the terms “subject” and “patient” are usedinterchangeably to refer to an animal or any living organism havingsensation and the power of voluntary movement, and which requires forits existence oxygen and organic food. Non-limiting examples includemembers of the human, equine, porcine, bovine, rattus, murine, canineand feline species. In one aspect, the subject is a mammal or awarm-blooded vertebrate animal. In another aspect, the subject is anon-human animal. In another aspect, the subject is a human.

As used herein, the term “RNA” means a molecule comprising at least oneribonucleotide residue. By “ribonucleotide” is meant a nucleotide with ahydroxyl group at the 2′ position of a beta-D-ribo-furanose moiety. Theterms include double stranded RNA, single stranded RNA, isolated RNAsuch as partially purified RNA, essentially pure RNA, synthetic RNA,recombinantly produced RNA, as well as altered RNA that differs fromnaturally occurring RNA by the addition, deletion, substitution and/oralteration of one or more nucleotides. RNAs can be synthesized in a cellby RNA polymerase I, II or III.

The term “mRNA” refers to any RNA that is produced in a cell by RNApolymerase II transcription of a gene. In one aspect, the mRNA of thedisclosure is capped and polyadenylated. In one aspect, an mRNA of thedisclosure encodes one or more proteins. In one aspect, the mRNA doesnot encode a protein. In another aspect, mRNA can refer to processed orunprocessed pre-mRNA. In another aspect, the mRNA of this disclosureincludes, but is not limited to, pre-mRNA, spliced mRNA, partiallyspliced mRNA and alternatively spliced mRNA. In one aspect, the mRNA ofthe disclosure is a transcript that undergoes nonsense-mediated decay(NMD) in the presence of a compound as described herein.

Splicing is a natural biological mechanism that may occur within humancells. Splicing processes primary messenger ribonucleic acid (mRNA) thathas been transcribed from deoxyribonucleic acid (DNA) before the mRNA istranslated into a protein. Splicing involves removing one or morecontiguous segments of mRNA and is directed, in part, by a spliceosome.The segments that are removed are often referred to as introns, but thespliceosome may remove segments that contain both introns and exons.

As used herein, the term “functional protein” refers to a form of aprotein that retains a certain biological function or the functions of afull length protein or protein isoform encoded by a gene. As usedherein, in the context of the use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I) to produce afunctional protein, wherein the amount of functional protein produced inthe absence of Compound (I) is at least 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 100% lessthan the amount of functional protein produced in the presence ofCompound (I).

As used herein, in the context of Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I) to produce a functional protein,and wherein the amount of functional protein produced in the absence ofCompound (I) is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 100% less than theamount of functional protein produced in the presence of Compound (I).

As used herein, the term “exon” refers to any part of a gene that is apart of the final mature RNA produced by that gene after introns havebeen removed by RNA splicing. The term “exon” refers to both the DNAsequence within a gene and to the corresponding sequence in RNAtranscripts.

As used herein, the term “intron” refers to both the DNA sequence withina gene and the corresponding sequence in the unprocessed RNA transcript.As part of the RNA processing pathway, introns can be removed by RNAsplicing either shortly after or concurrent with transcription.

As used herein, the term “isolated” means the physical state of Compound(I) after being isolated and/or purified from a synthetic process (e.g.,from a reaction mixture) or natural source or combination thereofaccording to an isolation or purification process or processes describedherein or which are well known to the skilled artisan (e.g.,chromatography, recrystallization and the like) in sufficient purity tobe characterized by standard analytical techniques described herein orwell known to the skilled artisan.

As used herein, the term “exon triplet” refers to three consecutiveexons in a gene transcript, each separated by adjacent introns. Oneaspect described herein includes a gene transcript of interestcomprising an exon triplet for interrogation by the CNN model asdescribed herein.

As used herein, the term “5-mer enrichment analysis” refers to 5-mersets of nucleotides identified as adjacent nucleotides from the −3 to +7position in a splice site junction known by those skilled in the art tohave an observed frequency of Class Effect greater than mere chancetoward modulating the splicing reaction. Such 5-mer sets of nucleotideshaving a frequency p value<0.05 toward a particular Class Effect weredeemed to be enriched.

As used herein, the term “LOGO plot” refers to the presentation of anucleotide sequence known by those skilled in the art to show analignment of nucleotides having a particular Class Effect. In one aspectdescribed herein, the representation of nucleotides in a LOGO plotsequence may show only one nucleotide in a LOGO plot position. Inanother aspect described herein, the representation of nucleotides in aLOGO plot sequence may show one or more nucleotides having differingheights in a LOGO plot position. In another aspect described herein, therepresentation of nucleotides in a LOGO plot sequence may show novisible nucleotide in a LOGO plot position. Accordingly, nucleotidesshown in a LOGO plot position represent potential variability for thenucleotide to be in that position. It is assumed by those skilled in theart that the probability for each one of the four possible nucleotidesto be present in any one position is assumed to be equally random, atleast 25% of the time. As used herein, the term “constant,” in referenceto a nucleotide in a particular LOGO plot position having only onenucleotide, indicates that the probability of the nucleotide to bepresent in that position is predicted to be 100%. In a LOGO plotpresented herein, the constant nucleotide is shown by a capital letterrepresenting the corresponding nucleotide. As used herein, the term“most dominant,” in reference to a nucleotide in a particular LOGO plotposition having no clear constant nucleotide, where more than onenucleotide is present as shown in a vertical nucleotide stack, indicatesthat the probability of one or more nucleotides to be present in thatposition is predicted to be less than 100%. In a LOGO plot presentedherein, the most dominant nucleotide is taken to be the topmostnucleotide in the LOGO plot position and is shown by a capital letterrepresenting the corresponding nucleotide. In other instances, where novisible nucleotide appears in a LOGO plot position, the position isshown by the capital letter “N”.

As used herein, the term “Class” refers to exclusion or inclusion of anexon in an mRNA splicing reaction in the presence of a small moleculesplicing compound to produce one or more mature RNA isoforms that areunlike an isoform produced by the wildtype or mutant gene transcript. Inanother aspect described herein, the effect may be the production of oneor more mature RNA isoforms unchanged from the wildtype or mutantspliced isoform.

As used herein, the term “Class Effect” refers to the production of oneor more mature RNA isoforms from a wildtype or mutant gene transcript inthe presence of a 5-mer nucleotide sequence identified or predicted tohave an effect toward exclusion or inclusion of an exon in an mRNAsplicing reaction while in the presence of a small molecule splicingcompound. In another aspect described herein, the predicted effect maybe the production of one or more mature RNA isoforms unchanged from thewildtype or mutant spliced isoform.

As used herein, the terms “Active Class” and “Active Class Effect” referto a set of 5-mer nucleotide sequences having a Class Effect on mRNAsplicing in the presence of a small molecule splicing compound towardexclusion or inclusion of an exon in an mRNA splicing reaction in thepresence of a small molecule splicing compound to produce one or moremature RNA isoforms from the wildtype or mutant gene transcript.

As used herein, the terms “Unchanged Class” and “Unchanged Class Effect”refer to a set of 5-mer nucleotide sequences having a Class Effecttoward exclusion or inclusion of an exon in an mRNA splicing reaction inthe presence of a small molecule splicing compound to produce one ormore mature RNA isoforms that are unchanged from those produced by thewildtype or mutant gene transcript in the absence of the small moleculesplicing compound.

As used herein, the term “Enrichment Motif” refers to a 5-mer nucleotidesequence identified in an enrichment analysis as described herein areknown to have a certain Class Effect on mRNA splicing in the presence ofa small molecule splicing compound. In one aspect described herein, anEnrichment Motif relates to a set of 5-mer nucleotide sequencesidentified as having an Active Class Effect. In another aspect describedherein, an Enrichment Motif relates to a set of 5-mer nucleotidesequences identified as having an Unchanged Class Effect. In anotheraspect described herein, all nucleotides in an Enrichment Motif areassumed to contribute to the frequency of the Enrichment Motif as a unittoward a particular Class Effect. In another aspect described herein,LOGO plots for Enrichment Motifs may show nucleotides having varyingheights, where the nucleotide in the position may have either a greateror lesser frequency toward having a certain Class Effect. In anotheraspect described herein, Constant nucleotides or More Dominantnucleotides shown in Enrichment Motif LOGO plots indicate those singlenucleotides have a greater frequency toward having an Active ClassEffect. In another aspect described herein, positions absent anucleotide shown in the Enrichment Motif LOGO plot indicate nucleotidesin those positions have an Unchanged Class Effect, having no frequencycontribution toward an Active Class Effect.

As used herein, the term “CNN Motif” refers to a 5-mer nucleotidesequence identified and predicted by the CNN model described herein tohave a Class Effect on mRNA splicing in the presence of a small moleculesplicing compound. In one aspect described herein, the CNN Model wastaught to convolute 400-mer sequences containing Enrichment Motifs intoseparate elements, where the position of each element could be analyzedas to whether the element in that position could contribute to a correctprediction toward a particular Class Effect. In another aspect describedherein, once built, the CNN Model was used to weight the predictivecontribution of every five nucleotides (5-mer) in the 400-mer through aconvolution process. Each position within a 5-mer was individuallyweighted according to potential contribution to a correct predictiontoward a particular Class Effect. As a result, certain 5-mer nucleotidepositions having a more predictive effect were identified, enablingthese 5-mer positions to be more preferentially weighted. In anotheraspect described herein, without being limited in any way by theory inany aspect of the CNN Model, the positional analysis convoluted by theCNN Model suggested that nucleotides in the −3 to +2 region of thesplice junction were more heavily weighted. In another aspect describedherein, the convoluted, highly weighted 5-mer nucleotide positions wereextracted from the CNN model and converted into CNN motifs according tothe weight at each position. In another aspect described herein,multiple CNN Motifs may be convoluted using the CNN Model describedherein to weight nucleotides in a gene sequence of interest to predictwhether a Class Effect will occur. For each CNN Motif, a single overallClass Effect for the CNN Motif was calculated, ranking the statisticalprobability of the CNN Motif to correctly predict a single overall ClassEffect based on the statistical probability resulting from theparticular analytical method used. In another aspect described herein,the frequency of an Enrichment Motif to have a particular Class Effectmay be compared with the probability of a similar or dissimilar CNNmotif to correctly predict a particular Class Effect using a PearsonCorrelation. In one aspect described herein, a CNN Motif relates to aset of 5-mer nucleotide sequences identified as having an Active ClassEffect. In one aspect described herein, a CNN Motif relates to a set of5-mer nucleotide sequences identified as having an Unchanged ClassEffect. In another aspect described herein, LOGO plots for CNN Motifsmay show nucleotides having varying heights, where the nucleotide in theposition may have either a greater or lesser positional importancetoward a predicting a certain Class Effect. In another aspect describedherein, Constant nucleotides and More Dominant nucleotides in a CNNMotif identified by the CNN model may be expected to have a positionalimportance toward a Class Effect. In another aspect described herein,one or more of either or both Constant nucleotides and More Dominantnucleotides in a deconvoluted CNN Motif LOGO plot may influenceprediction toward a variety of Active Class Effects, the convoluted CNNMotif may have a greater positional importance toward predicting asingle overall Active Class Effect. In another aspect described herein,positions absent a nucleotide shown in the CNN Motif LOGO plot indicatesingle nucleotides in those positions have an Unchanged Class Effect,where the open positions have no positional importance toward predictingan overall Active Class Effect.

As used herein, the term “Pearson Correlation” refers to a statisticalcorrelation comparing the Class Effect of an Enrichment Motif with a CNNMotif. The Pearson Correlation compares the overall Class Effectpredicted by an individual CNN Motif with the frequency of Class Effectfor an individual Enrichment Motif. In another aspect described herein,the Pearson Correlation for an Enrichment Motif may show a Positive orNegative Correlation to a Class Effect for a similar or dissimilar CNNMotif.

As used herein, the phrase “predicted wildtype or mutant genetranscript” refers to a gene transcript containing a 5-mer nucleotidesequence identified as having a predicted Class Effect toward exclusionor inclusion of an exon in an mRNA splicing reaction in the presence ofa small molecule splicing compound to produce one or more mature RNAisoforms from the wildtype or mutant gene transcript. In one aspectdescribed herein, the predicted effect of the 5-mer nucleotide sequencemay be identified using a CNN model or equivalents thereof which arewithin the scope of one skilled in the art to design. In another aspectdescribed herein, the predicted effect of the 5-mer nucleotide sequencemay be identified in an enrichment analysis using methods known to thoseskilled in the art.

Pharmaceutical Compositions and Modes of Administration

When administered to a patient, Compound (I) is preferably administeredas a component of a composition that optionally comprises apharmaceutically acceptable carrier, excipient or diluent. Thecomposition can be administered orally, or by any other convenientroute, for example, by infusion or bolus injection, by absorptionthrough epithelial or mucocutaneous linings (e.g., oral mucosa, rectal,and intestinal mucosa) and may be administered together with anotherbiologically active agent. Administration can be systemic or local.Various delivery systems are known, e.g., encapsulation in liposomes,microparticles, microcapsules, capsules, and can be used to administerthe compound.

Methods of administration include, but are not limited to, parenteral,intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous,intranasal, epidural, oral, sublingual, intranasal, intraocular,intratumoral, intracerebral, intravaginal, transdermal, ocularly,rectally, by inhalation, or topically, particularly to the ears, nose,eyes, or skin. The mode of administration is left to the discretion ofthe practitioner. In most instances, administration will result in therelease of a compound into the bloodstream, tissue or cell(s). In aspecific aspect, a compound is administered orally.

The amount of Compound (I) that will be effective in the treatment of adisease resulting from an aberrant amount of mRNA transcripts depends,e.g., on the route of administration, the disease being treated, thegeneral health of the subject, ethnicity, age, weight, and gender of thesubject, diet, time, and the severity of disease progress, and should bedecided according to the judgment of the practitioner and each patient'sor subject's circumstances.

In specific aspects, an “effective amount” in the context of theadministration of Compound (I), or composition or medicament thereofrefers to an amount of Compound (I) to a patient which has a therapeuticeffect and/or beneficial effect. In certain specific aspects, an“effective amount” in the context of the administration of Compound (I),or composition or medicament thereof to a patient results in one, two ormore of the following effects: (i) reduces or ameliorates the severityof a disease; (ii) delays onset of a disease; (iii) inhibits theprogression of a disease; (iv) reduces hospitalization of a subject; (v)reduces hospitalization length for a subject; (vi) increases thesurvival of a subject; (vii) improves the quality of life of a subject;(viii) reduces the number of symptoms associated with a disease; (ix)reduces or ameliorates the severity of a symptom(s) associated with adisease; (x) reduces the duration of a symptom associated with a diseaseassociated; (xi) prevents the recurrence of a symptom associated with adisease; (xii) inhibits the development or onset of a symptom of adisease; and/or (xiii) inhibits of the progression of a symptomassociated with a disease. In certain aspects, an effective amount ofCompound (I) is an amount effective to restore the amount of a RNAtranscript of a gene to the amount of the RNA transcript detectable inhealthy patients or cells from healthy patients. In other aspects, aneffective amount of Compound (I) is an amount effective to restore theamount an RNA isoform and/or protein isoform of gene to the amount ofthe RNA isoform and/or protein isoform detectable in healthy patients orcells from healthy patients.

In certain aspects, an effective amount of Compound (I) is an amounteffective to decrease the aberrant amount of an RNA transcript of a genewhich associated with a disease. In certain aspects, an effective amountof Compound (I) is an amount effective to decrease the amount of theaberrant expression of an isoform of a gene. In some aspects, aneffective amount of Compound (I) is an amount effective to result in asubstantial change in the amount of an RNA transcript (e.g., mRNAtranscript), alternative splice variant or isoform.

In certain aspects, an effective amount of Compound (I) is an amounteffective to increase or decrease the amount of an RNA transcript (e.g.,an mRNA transcript) of gene which is beneficial for the preventionand/or treatment of a disease. In certain aspects, an effective amountof Compound (I) is an amount effective to increase or decrease theamount of an alternative splice variant of an RNA transcript of genewhich is beneficial for the prevention and/or treatment of a disease. Incertain aspects, an effective amount of Compound (I) is an amounteffective to increase or decrease the amount of an isoform of gene whichis beneficial for the prevention and/or treatment of a disease.Non-limiting examples of effective amounts of Compound (I) are describedherein.

For example, the effective amount may be the amount required to preventand/or treat a disease associated with the aberrant amount of an mRNAtranscript of gene in a human subject.

In general, the effective amount will be in a range of from about 0.001mg/kg/day to about 500 mg/kg/day for a patient having a weight in arange of between about 1 kg to about 200 kg. The typical adult subjectis expected to have a median weight in a range of between about 70 andabout 100 kg.

Within the scope of the present description, the “effective amount” ofCompound (I) for use in the manufacture of a medicament, the preparationof a pharmaceutical kit or in a method for preventing and/or treating adisease in a human subject in need thereof, is intended to include anamount in a range of from about 0.001 mg to about 35,000 mg.

The compositions described herein are formulated for administration tothe subject via any drug delivery route known in the art. Non-limitingexamples include oral, ocular, rectal, buccal, topical, nasal,ophthalmic, subcutaneous, intramuscular, intravenous (bolus andinfusion), intracerebral, transdermal, and pulmonary routes ofadministration.

Aspects described herein include the use of Compound (I) in apharmaceutical composition. In a specific aspect, described herein isthe use of Compound (I) in a pharmaceutical composition for preventingand/or treating a disease in a human subject in need thereof comprisingadministering an effective amount of Compound (I) in admixture with apharmaceutically acceptable carrier, excipient or diluent. In a specificaspect, the human subject is a patient with a disease associated withthe aberrant amount of an mRNA transcript(s).

Compound (I) may optionally be in the form of a composition comprisingthe compound or a form thereof and an optional carrier, excipient, ordiluent. Other aspects provided herein include pharmaceuticalcompositions comprising an effective amount of Compound (I) and apharmaceutically acceptable carrier, excipient, or diluent. In aspecific aspect, the pharmaceutical compositions are suitable forveterinary and/or human administration. The pharmaceutical compositionsprovided herein can be in any form that allows for the composition to beadministered to a subject.

In a specific aspect and in this context, the term “pharmaceuticallyacceptable carrier, excipient or diluent” means a carrier, excipient ordiluent approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals, and more particularly inhumans. The term “carrier” refers to a diluent, adjuvant (e.g., Freund'sadjuvant (complete and incomplete)), excipient, or vehicle with which atherapeutic agent is administered. Such pharmaceutical carriers can besterile liquids, such as water and oils, including those of petroleum,animal, vegetable, or synthetic origin, such as peanut oil, soybean oil,mineral oil, sesame oil and the like. Water is a specific carrier forintravenously administered pharmaceutical compositions. Saline solutionsand aqueous dextrose and glycerol solutions can also be employed asliquid carriers, particularly for injectable solutions.

Typical compositions and dosage forms comprise one or more excipients.Suitable excipients are well-known to those skilled in the art ofpharmacy, and non limiting examples of suitable excipients includestarch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patientand the specific active ingredients in the dosage form. Further providedherein are anhydrous pharmaceutical compositions and dosage formscomprising Compound (I) as described herein. The compositions and singleunit dosage forms can take the form of solutions or syrups (optionallywith a flavoring agent), suspensions (optionally with a flavoringagent), emulsions, tablets (e.g., chewable tablets), pills, capsules,granules, powder (optionally for reconstitution), taste-masked orsustained-release formulations and the like.

Pharmaceutical compositions provided herein that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets, caplets, capsules, granules, powder, andliquids. Such dosage forms contain predetermined amounts of activeingredients, and may be prepared by methods of pharmacy well known tothose skilled in the art.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants.

In another aspect, the method for modulating the amount of one, two,three or more RNA transcripts of a gene described herein, comprisingcontacting a cell with Compound (I) includes a cell in a cell culture.In other aspects, the cell is contacted with Compound (I) in a subject(e.g., a non-human animal subject or a human subject).

In certain aspects described herein, the cell(s) is contacted orcultured with Compound (I) with Compound (I) for a period of 15 minutes,30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6hours, 8 hours, 12 hours, 18 hours, 24 hours, 48 hours, 72 hours ormore. In other aspects described herein, the cell(s) is contacted orcultured with Compound (I) with Compound (I) for a period of 15 minutesto 1 hour, 1 to 2 hours, 2 to 4 hours, 6 to 12 hours, 12 to 18 hours, 12to 24 hours, 28 to 24 hours, 24 to 48 hours, 48 to 72 hours.

In certain aspects described herein, the cell(s) is contacted orcultured with a certain concentration of Compound (I), wherein thecertain concentration is 0.01 μM, 0.05 μM, 1 μM, 2 μM, 5 μM, 10 μM, 15μM, 20 μM, 25 μM, 50 μM, 75 μM, 100 μM, or 150 μM. In other aspectsdescribed herein, the cell(s) is contacted or cultured with a certainconcentration of Compound (I), wherein the certain concentration is 175μM, 200 μM, 250 μM, 275 μM, 300 μM, 350 μM, 400 μM, 450 μM, 500 μM, 550μM 600 μM, 650 μM, 700 μM, 750 μM, 800 μM, 850 μM, 900 μM, 950 μM or 1mM. In some aspects described herein, the cell(s) is contacted orcultured with a certain concentration of Compound (I), wherein thecertain concentration is 5 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM,70 nM, 80 nM, 90 nM, 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM, 400nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850nM, 900 nM, or 950 nM. In certain aspects described herein, the cell(s)is contacted or cultured with a certain concentration of Compound (I),wherein the certain concentration is between 0.01 μM to 0.1 μM, 0.1 μMto 1 μM, 1 μM to 50 μM, 50 μM to 100 μM, 100 μM to 500 μM, 500 μM to 1nM, 1 nM to 10 nM, 10 nM to 50 nM, 50 nM to 100 nM, 100 nM to 500 nM,500 nM to 1000 nM. In certain aspects described herein, the cell(s) iscontacted or cultured with a certain concentration of Compound (I) thatresults in a substantial change in the amount of an RNA transcript(e.g., an mRNA transcript), an alternatively spliced variant, or anisoform of a gene (e.g., a gene described herein, infra).

In another aspect, provided herein are methods for modulating the amountof one, two, three or more RNA transcripts of a gene, comprisingadministering to a human or non-human subject Compound (I), or apharmaceutical composition comprising Compound (I) and apharmaceutically acceptable carrier, excipient or diluent.

In one aspect, provided herein are methods for modulating the amount ofone, two, three or more RNA transcripts of a gene described herein, themethods comprising administering to a human or non-human subjectCompound (I), or a pharmaceutical composition comprising Compound (I)and a pharmaceutically acceptable carrier, excipient or diluent.

In certain aspects, Compound (I) contacted or cultured with a cell(s) oradministered to a subject is a compound as described herein.

Compound (I) Use in a Method

One aspect described herein is Compound (I) for use in a method tomodulate the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I).

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a wildtype gene transcript comprising,three exons and two introns operably linked in the following order: Exon1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice siteof Exon 2 comprises, a sequence selected from the group consisting of:CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQID NO: 3), and CCAgtgagga (SEQ ID NO: 4).

(SEQ ID NO: 1) CAAgtaagt, (SEQ ID NO: 2) GATTAAgtgggt, (SEQ ID NO: 3)CACTAGgtgaga, and (SEQ ID NO: 4) CCAgtgagga.

Another aspect described herein is Compound (I) for use in the method,wherein the 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ IDNO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8).

(SEQ ID NO: 5) CAAguaagu, (SEQ ID NO: 6) GAUUAAgugggu, (SEQ ID NO: 7)CACUAGgugaga, and (SEQ ID NO: 8) CCAgugagga.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a mutant gene transcript comprising,three exons and two introns operably linked in the following order: Exon1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice siteof Exon 2 comprises, a sequence selected from the group consisting of:

(SEQ ID NO: 9) CAAgtaagc, (SEQ ID NO: 10) GATTAAgtaggt, (SEQ ID NO: 11)CACTAGgtgagc, (SEQ ID NO: 12) CCAgttagga, (SEQ ID NO: 13) AGCCAAgtatgt,(SEQ ID NO: 14) ATCCAAgtatgt, (SEQ ID NO: 15) CTGAAgtcagt, and(SEQ ID NO: 16) AGTgtaagta.

Another aspect described herein is Compound (I) for use in the method,wherein the 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of:

(SEQ ID NO: 17) CAAguaagc, (SEQ ID NO: 18) GAUUAAguaggu, (SEQ ID NO: 19)CACUAGgugagc, (SEQ ID NO: 20) CCAguuagga, (SEQ ID NO: 21) AGCCAAguaugu,(SEQ ID NO: 22) AUCCAAguaugu, (SEQ ID NO: 23) CUGAAgucagu, and(SEQ ID NO: 24) AGUguaagua.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a sequence selected from the groupconsisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ IDNO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO:33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO:36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO:39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO:42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO:45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO:48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO:51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO:54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO:57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO:60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO:63), and wherein N represents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a sequence selected from the groupconsisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ IDNO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO:35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO:40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO:44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO:48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO:52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO:56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO:59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), and wherein Nrepresents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a sequence selected from the groupconsisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ IDNO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO:73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO:76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO:80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO:84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO:87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO:90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO:93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO:98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO:101), and CUGUA (SEQ ID NO: 102), and wherein N represents any RNAnucleotide.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a sequence selected from the groupconsisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ IDNO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO:74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO:82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO:86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO:90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO:95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO:100), and CUGUA (SEQ ID NO: 102), and wherein N represents any RNAnucleotide.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,and wherein a 5′ splice site of Exon 2 comprises, a sequence other thana sequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4).

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,and wherein a 5′ splice site of Exon 2 comprises, a sequence other thana sequence selected from the group consisting of:

(SEQ ID NO: 5) CAAguaagu, (SEQ ID NO: 6) GAUUAAgugggu, (SEQ ID NO: 7)CACUAGgugaga, and (SEQ ID NO: 8) CCAgugagga.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,and wherein a 5′ splice site of Exon 2 comprises, a sequence other thana sequence selected from the group consisting of:

(SEQ ID NO: 9) CAAgtaagc, (SEQ ID NO: 10) GATTAAgtaggt, (SEQ ID NO: 11)CACTAGgtgagc, (SEQ ID NO: 12) CCAgttagga, (SEQ ID NO: 13) AGCCAAgtatgt,(SEQ ID NO: 14) ATCCAAgtatgt, (SEQ ID NO: 15) CTGAAgtcagt, and(SEQ ID NO: 16) AGTgtaagta.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,and wherein a 5′ splice site of Exon 2 comprises, a sequence other thana sequence selected from the group consisting of:

(SEQ ID NO: 17) CAAguaagc, (SEQ ID NO: 18) GAUUAAguaggu, (SEQ ID NO: 19)CACUAGgugagc, (SEQ ID NO: 20) CCAguuagga, (SEQ ID NO: 21) AGCCAAguaugu,(SEQ ID NO: 22) AUCCAAguaugu, (SEQ ID NO: 23) CUGAAgucagu, and(SEQ ID NO: 24) AGUguaagua.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell with Compound(I).

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon inclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I).

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon exclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I).

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell in vivo or invitro with Compound (I).

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, and wherein the subject is human.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, and wherein one or more of the mature RNAisoforms produce a functional protein.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell, andwherein the gene transcript is transcribed from a gene selected fromTable 14.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having the mutated transcript is selected from the groupconsisting of Table 14 and 15.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having the mutated transcript is selected from the groupconsisting of Table 14.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having the mutated transcript is other than the geneselected from the group consisting of Table 15.

Use of Compound (I)

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I).

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAgtaagt(SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO:3), and CCAgtgagga (SEQ ID NO: 4).

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAguaagu(SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO:7), and CCAgugagga (SEQ ID NO: 8).

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAgtaagc(SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO:11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13),ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16).

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAguaagc(SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO:19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21),AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), andAGUguaagua (SEQ ID NO: 24).

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27),CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30),TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33),TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36),TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39),GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42),AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51),TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54),GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57),CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60),AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63),and wherein N represents any DNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), and wherein Nrepresents any DNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence other than a sequence selected from the groupconsisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2),CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4).

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence other than a sequence selected from the groupconsisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6),CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8).

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence other than a sequence selected from the groupconsisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10),CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt(SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO:15), and AGTgtaagta (SEQ ID NO: 16).

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence other than a sequence selected from the groupconsisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18),CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu(SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO:23), and AGUguaagua (SEQ ID NO: 24).

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell with Compound(I).

Another aspect described herein is use of Compound (I) to increase exoninclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I).

Another aspect described herein is use of Compound (I) to increase exonexclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I).

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell in vivo or invitro with Compound (I).

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript, andwherein the subject is human.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript, andwherein one or more of the mature RNA isoforms produce a functionalprotein.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, modulating the production ofone or more mature RNA isoforms from a gene transcript by administeringto the subject a pharmaceutical composition of Compound (I) and apharmaceutically acceptable carrier, excipient, or diluent, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript.

Another aspect described herein is use of Compound (I), wherein a genehaving the mutated transcript is selected from the group consisting ofTable 14 and 15.

Another aspect described herein is use of Compound (I), wherein a genehaving the mutated transcript is selected from the group consisting ofTable 14.

Another aspect described herein is use of Compound (I), wherein a genehaving the mutated transcript is other than the gene selected from thegroup consisting of Table 15.

Compound (I) Use in a Method

One aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I).

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from awildtype gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the wildtype genetranscript comprises, three exons and two introns operably linked in thefollowing order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, andwherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ IDNO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4).

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from awildtype gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the wildtype genetranscript comprises, three exons and two introns operably linked in thefollowing order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, andwherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ IDNO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8).

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from amutant gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the mutant genetranscript comprises, three exons and two introns operably linked in thefollowing order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, andwherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ IDNO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12),AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt(SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16).

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from amutant gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the mutant genetranscript comprises, three exons and two introns operably linked in thefollowing order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, andwherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ IDNO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20),AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu(SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24).

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from apredicted wildtype or mutant gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein thepredicted wildtype or mutant gene transcript includes a nucleotidesequence selected from the group consisting of: CTTAG (SEQ ID NO: 25),NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO: 31),TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34),TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO: 37),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43),GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO: 46),TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49),AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55),NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58),NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO: 61),ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), and wherein Nrepresents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from apredicted wildtype or mutant gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein thepredicted wildtype or mutant gene transcript includes a nucleotidesequence selected from the group consisting of: NNAGC (SEQ ID NO: 26),NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29),TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33),TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38),GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42),AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46),TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49),GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54),GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57),CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), andCTGTA (SEQ ID NO: 63), and wherein N represents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from apredicted wildtype or mutant gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein thepredicted wildtype or mutant gene transcript includes a nucleotidesequence selected from the group consisting of: CUUAG (SEQ ID NO: 64),NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77),GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85),UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88),AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91),AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99),AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO:102), and wherein N represents any RNA nucleotide.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from apredicted wildtype or mutant gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein thepredicted wildtype or mutant gene transcript includes a nucleotidesequence selected from the group consisting of: NNAGC (SEQ ID NO: 65),NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68),UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72),UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77),GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91),UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96),NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO:102), and wherein N represents any RNA nucleotide.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from apredicted wildtype or mutant gene transcript in a cell, wherein themethod comprises, contacting the cell with Compound (I), wherein thepredicted wildtype or mutant gene transcript includes a nucleotidesequence selected from the group consisting of: CUUAG (SEQ ID NO: 64),NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), GCAGA (SEQ ID NO: 69), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), GAGAG (SEQ ID NO: 79),AGGAN (SEQ ID NO: 80), AGACC (SEQ ID NO: 81), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85),UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88),AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91),AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), GGGAA (SEQ ID NO: 94),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), CAGGC (SEQ ID NO: 97),NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100),ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), and wherein Nrepresents any RNA nucleotide.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from awildtype gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the wildtype genetranscript comprises, three exons and two introns operably linked in thefollowing order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, andwherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of:

(SEQ ID NO: 1) CAAgtaagt, (SEQ ID NO: 2) GATTAAgtgggt, (SEQ ID NO: 3)CACTAGgtgaga, and (SEQ ID NO: 4) CCAgtgagga.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from awildtype gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the wildtype genetranscript comprises, three exons and two introns operably linked in thefollowing order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, andwherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of:

(SEQ ID NO: 5) CAAguaagu, (SEQ ID NO: 6) GAUUAAgugggu, (SEQ ID NO: 7)CACUAGgugaga, and (SEQ ID NO: 8) CCAgugagga.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from amutant gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the mutant genetranscript comprises, three exons and two introns operably linked in thefollowing order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, andwherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of:

(SEQ ID NO: 9) CAAgtaagc, (SEQ ID NO: 10) GATTAAgtaggt, (SEQ ID NO: 11)CACTAGgtgagc, (SEQ ID NO: 12) CCAgttagga, (SEQ ID NO: 13) AGCCAAgtatgt,(SEQ ID NO: 14) ATCCAAgtatgt, (SEQ ID NO: 15) CTGAAgtcagt, and(SEQ ID NO: 16) AGTgtaagta.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from amutant gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the mutant genetranscript comprises, three exons and two introns operably linked in thefollowing order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, andwherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of:

(SEQ ID NO: 17) CAAguaagc, (SEQ ID NO: 18) GAUUAAguaggu, (SEQ ID NO: 19)CACUAGgugagc, (SEQ ID NO: 20) CCAguuagga, (SEQ ID NO: 21) AGCCAAguaugu,(SEQ ID NO: 22) AUCCAAguaugu, (SEQ ID NO: 23) CUGAAgucagu, and(SEQ ID NO: 24) AGUguaagua.

Another aspect described herein is Compound (I) for use in a method formodulating exon inclusion or exon exclusion in one or more mature RNAisoforms from a gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I).

Another aspect described herein is Compound (I) for use in a method forincreasing exon inclusion in one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I).

Another aspect described herein is Compound (I) for use in a method forincreasing exon exclusion in one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I).

Another aspect described herein is Compound (I) for use in a method formodulating exon inclusion or exon exclusion in one or more mature RNAisoforms from a gene transcript in a cell, wherein the method comprises,contacting the cell in vivo or in vitro with Compound (I).

Another aspect described herein is Compound (I) for use in a method fortreating a disease associated with or mediated by a mutation in a genetranscript in a subject in need thereof, wherein the method comprises,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, and wherein the subject is human.

Another aspect described herein is Compound (I) for use in a method fortreating a disease associated with or mediated by a mutation in a genetranscript in a subject in need thereof, wherein the method comprises,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, and wherein one or more of the mature RNAisoforms produce a functional protein.

Another aspect described herein is Compound (I) for use in a method fortreating a disease associated with or mediated by a mutation in a genetranscript in a subject in need thereof, wherein the method comprises,modulating the production of one or more mature RNA isoforms from a genetranscript by administering to the subject a pharmaceutical compositionof Compound (I) and a pharmaceutically acceptable carrier, excipient, ordiluent, wherein exon inclusion or exon exclusion is modulated in one ormore mature RNA isoforms produced from the gene transcript.

Methods for Modulating Isoform Production

One aspect described herein is a method for modulating the production ofone or more mature RNA isoforms from a gene transcript in a cellcomprising, contacting the cell with Compound (I).

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAgtaagt(SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO:3), and CCAgtgagga (SEQ ID NO: 4).

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAguaagu(SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO:7), and CCAgugagga (SEQ ID NO: 8).

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAgtaagc(SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO:11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13),ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16).

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAguaagc(SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO:19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21),AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), andAGUguaagua (SEQ ID NO: 24).

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27),CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30),TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33),TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36),TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39),GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42),AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51),TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54),GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57),CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60),AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63),and wherein N represents any DNA nucleotide.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), and wherein Nrepresents any DNA nucleotide.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), and wherein N represents any RNA nucleotide.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence other than a sequence selected from the groupconsisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2),CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4).

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence other than a sequence selected from the groupconsisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6),CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8).

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence other than a sequence selected from the groupconsisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10),CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt(SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO:15), and AGTgtaagta (SEQ ID NO: 16).

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence other than a sequence selected from the groupconsisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18),CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu(SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO:23), and AGUguaagua (SEQ ID NO: 24).

Another aspect described herein is a method for modulating exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell with Compound(I).

Another aspect described herein is a method for increasing exoninclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I).

Another aspect described herein is a method for increasing exonexclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I).

Another aspect described herein is a method for modulating exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell in vivo or invitro with Compound (I).

Another aspect described herein is a method for treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof comprising, administering Compound (I) to thesubject, wherein exon inclusion or exon exclusion is modulated in one ormore mature RNA isoforms produced from the gene transcript, and whereinthe subject is human.

Another aspect described herein is a method for treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof comprising, administering Compound (I) to thesubject, wherein exon inclusion or exon exclusion is modulated in one ormore mature RNA isoforms produced from the gene transcript, and whereinone or more of the mature RNA isoforms produce a functional protein.

Another aspect described herein is a method for treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof comprising, modulating the production of one ormore mature RNA isoforms from a gene transcript by administering to thesubject a pharmaceutical composition of Compound (I) and apharmaceutically acceptable carrier, excipient, or diluent, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript.

Compound (I) Use in a Method

One aspect described herein is Compound (I) for use in a method tomodulate the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ IDNO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ IDNO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ IDNO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12),AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt(SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutantgene transcript is transcribed from a gene selected from Tables 1, 2, 3,4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ IDNO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20),AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu(SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutantgene transcript is transcribed from a gene selected from Tables 1, 2, 3,4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a predicted wildtype or mutant gene transcript in a cell,wherein the method comprises, contacting the cell with Compound (I),wherein the predicted wildtype or mutant gene transcript includes anucleotide sequence selected from the group consisting of: CTTAG (SEQ IDNO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO:28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO:31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO:34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO:37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO:40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO:43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO:46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO:49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO:52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO:55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO:58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO:61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), wherein Nrepresents any DNA nucleotide, and wherein the predicted wildtype ormutant gene transcript is transcribed from a gene selected from Tables1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a,10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a,10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of: CAAgtaagc (SEQ ID NO:9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11),CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt(SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO:16), and wherein the mutant gene transcript is transcribed from a geneselected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of: CAAguaagc (SEQ ID NO:17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19),CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu(SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO:24), and wherein the mutant gene transcript is transcribed from a geneselected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell with Compound(I), and wherein the gene transcript is transcribed from a gene selectedfrom Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon inclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) increases exon exclusion to produce one or moremature RNA isoforms from a gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), and wherein the genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates exon inclusion or exon exclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, wherein the method comprises, contacting the cell in vivo or invitro with Compound (I), and wherein the gene transcript is transcribedfrom a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12or 13.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein the subject is human, and wherein thegene transcript is transcribed from a gene selected from Tables 1, 2, 3,4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein one or more of the mature RNA isoformsproduce a functional protein, and wherein the gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a,10, 11, 12 or 13.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell, andwherein the gene transcript is transcribed from a gene selected fromTables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having the mutated transcript is selected from the groupconsisting of Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Methods for Modulating Isoform Production

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene selected from Tables 1, 2, 3,4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a,10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a,10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagc (SEQ ID NO:9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11),CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt(SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO:16), and wherein the mutant gene transcript is transcribed from a geneselected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagc (SEQ ID NO:17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19),CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu(SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO:24), and wherein the mutant gene transcript is transcribed from a geneselected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27),CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30),TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33),TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36),TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39),GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42),AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51),TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54),GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57),CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60),AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12or 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12or 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc(SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO:13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a,10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc(SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO:21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), andAGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a,10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell with Compound(I), wherein the gene transcript is transcribed from a gene selectedfrom Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to increase exoninclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to increase exonexclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to modulate exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell in vivo or invitro with Compound (I), wherein the gene transcript is transcribed froma gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or13.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript,wherein the subject is human, and wherein the gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a,10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript,wherein one or more of the mature RNA isoforms produce a functionalprotein, and wherein the gene transcript is transcribed from a geneselected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, modulating the production ofone or more mature RNA isoforms from a gene transcript by administeringto the subject a pharmaceutical composition of Compound (I) and apharmaceutically acceptable carrier, excipient, or diluent, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, and wherein the genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Compound (I) Use in a Method

One aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), wherein the gene transcript comprises, three exonsand two introns operably linked in the following order: Exon 1, Intron1, Exon 2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAgtaagt(SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO:3), and CCAgtgagga (SEQ ID NO: 4), and wherein the gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a,10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from awildtype gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the wildtype genetranscript comprises, three exons and two introns operably linked in thefollowing order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, whereina 5′ splice site of Exon 2 comprises, a sequence selected from the groupconsisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2),CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and whereinthe wildtype gene transcript is transcribed from a gene selected fromTables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from awildtype gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the wildtype genetranscript comprises, three exons and two introns operably linked in thefollowing order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, whereina 5′ splice site of Exon 2 comprises, a sequence selected from the groupconsisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6),CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), and whereinthe wildtype gene transcript is transcribed from a gene selected fromTables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from amutant gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the mutant genetranscript comprises, three exons and two introns operably linked in thefollowing order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, whereina 5′ splice site of Exon 2 comprises, a sequence selected from the groupconsisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10),CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt(SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO:15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutant genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from amutant gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the mutant genetranscript comprises, three exons and two introns operably linked in thefollowing order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, whereina 5′ splice site of Exon 2 comprises, a sequence selected from the groupconsisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18),CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu(SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO:23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutant genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from apredicted wildtype or mutant gene transcript in a cell comprising,contacting the cell with Compound (I), wherein the predicted wildtype ormutant gene transcript includes a nucleotide sequence selected from thegroup consisting of: CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA(SEQ ID NO: 27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA(SEQ ID NO: 30), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC(SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN(SEQ ID NO: 36), TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT(SEQ ID NO: 39), GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC(SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT(SEQ ID NO: 45), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG(SEQ ID NO: 51), TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT(SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC(SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT(SEQ ID NO: 60), AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA(SEQ ID NO: 63), wherein N represents any DNA nucleotide, and whereinthe predicted wildtype or mutant gene transcript is transcribed from agene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from apredicted wildtype or mutant gene transcript in a cell comprising,contacting the cell with Compound (I), wherein the predicted wildtype ormutant gene transcript includes a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from apredicted wildtype or mutant gene transcript in a cell comprising,contacting the cell with Compound (I), wherein the predicted wildtype ormutant gene transcript includes a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from apredicted wildtype or mutant gene transcript in a cell comprising,contacting the cell with Compound (I), wherein the predicted wildtype ormutant gene transcript includes a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), wherein N represents anyRNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from awildtype gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the wildtype genetranscript comprises, three exons and two introns operably linked in thefollowing order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, whereina 5′ splice site of Exon 2 comprises, a sequence other than a sequenceselected from the group consisting of: CAAgtaagt (SEQ ID NO: 1),GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga(SEQ ID NO: 4), and wherein the wildtype gene transcript is transcribedfrom a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12or 13.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from awildtype gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the wildtype genetranscript comprises, three exons and two introns operably linked in thefollowing order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, whereina 5′ splice site of Exon 2 comprises, a sequence other than a sequenceselected from the group consisting of: CAAguaagu (SEQ ID NO: 5),GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga(SEQ ID NO: 8), and wherein the wildtype gene transcript is transcribedfrom a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12or 13.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from amutant gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the mutant genetranscript comprises, three exons and two introns operably linked in thefollowing order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, whereina 5′ splice site of Exon 2 comprises, a sequence other than a sequenceselected from the group consisting of: CAAgtaagc (SEQ ID NO: 9),GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga(SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO:14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), andwherein the mutant gene transcript is transcribed from a gene selectedfrom Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method formodulating the production of one or more mature RNA isoforms from amutant gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), wherein the mutant genetranscript comprises, three exons and two introns operably linked in thefollowing order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, whereina 5′ splice site of Exon 2 comprises, a sequence other than a sequenceselected from the group consisting of: CAAguaagc (SEQ ID NO: 17),GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga(SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO:22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), andwherein the mutant gene transcript is transcribed from a gene selectedfrom Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method formodulating exon inclusion or exon exclusion in one or more mature RNAisoforms from a gene transcript in a cell, wherein the method comprises,contacting the cell with Compound (I), and wherein the gene transcriptis transcribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8,9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method forincreasing exon inclusion in one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method forincreasing exon exclusion in one or more mature RNA isoforms from a genetranscript in a cell, wherein the method comprises, contacting the cellwith Compound (I), and wherein the gene transcript is transcribed from agene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in a method formodulating exon inclusion or exon exclusion in one or more mature RNAisoforms from a gene transcript in a cell, wherein the method comprises,contacting the cell in vivo or in vitro with Compound (I), and whereinthe gene transcript is transcribed from a gene selected from Tables 1,2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, and wherein the gene transcript is transcribedfrom a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12or 13.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein the subject is human, and wherein thegene transcript is transcribed from a gene selected from Tables 1, 2, 3,4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, wherein one or more of the mature RNA isoformsproduce a functional protein, and wherein the gene is selected fromTables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell, andwherein the gene transcript is transcribed from a gene selected fromTables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having the mutated transcript is selected from Tables 1,2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13. METHODS FOR MODULATINGISOFORM PRODUCTION

One aspect described herein is a method for modulating the production ofone or more mature RNA isoforms from a gene transcript in a cellcomprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a gene transcript ina cell comprising, contacting the cell with Compound (I), wherein thegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ IDNO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), andwherein the gene transcript is transcribed from a gene selected fromTables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a,10, 11, 12 or 13.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a,10, 11, 12 or 13.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagc (SEQ ID NO:9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11),CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt(SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO:16), and wherein the mutant gene transcript is transcribed from a geneselected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagc (SEQ ID NO:17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19),CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu(SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO:24), and wherein the mutant gene transcript is transcribed from a geneselected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27),CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30),TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33),TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36),TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39),GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42),AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51),TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54),GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57),CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60),AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12or 13.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12or 13.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc(SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO:13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a,10, 11, 12 or 13.

Another aspect described herein is a method for modulating theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc(SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO:21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), andAGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript istranscribed from a gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a,10, 11, 12 or 13.

One aspect described herein is a method for modulating exon inclusion orexon exclusion in one or more mature RNA isoforms from a gene transcriptin a cell comprising, contacting the cell with Compound (I), wherein thegene transcript is transcribed from a gene selected from Tables 1, 2, 3,4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for increasing exoninclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for increasing exonexclusion in one or more mature RNA isoforms from a gene transcript in acell comprising, contacting the cell with Compound (I), wherein the genetranscript is transcribed from a gene selected from Tables 1, 2, 3, 4,5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for modulating exoninclusion or exon exclusion in one or more mature RNA isoforms from agene transcript in a cell comprising, contacting the cell in vivo or invitro with Compound (I), wherein the gene transcript is transcribed froma gene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or13.

Another aspect described herein is a method for treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof comprising, administering Compound (I) to thesubject, wherein exon inclusion or exon exclusion is modulated in one ormore mature RNA isoforms produced from the gene transcript, and whereinthe gene transcript is transcribed from a gene selected from Tables 1,2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof comprising, administering Compound (I) to thesubject, wherein exon inclusion or exon exclusion is modulated in one ormore mature RNA isoforms produced from the gene transcript, wherein thesubject is human, and wherein the gene transcript is transcribed from agene selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect described herein is a method for treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof comprising, administering Compound (I) to thesubject, wherein exon inclusion or exon exclusion is modulated in one ormore mature RNA isoforms produced from the gene transcript, wherein oneor more of the mature RNA isoforms produce a functional protein, andwherein the gene is selected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10,11, 12 or 13.

Another aspect described herein is a method for treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof comprising, modulating the production of one ormore mature RNA isoforms from a gene transcript by administering to thesubject a pharmaceutical composition of Compound (I) and apharmaceutically acceptable carrier, excipient, or diluent, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, and wherein the gene isselected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Methods for Treating a Disease

One aspect described herein is Compound (I) for use in a method, whereinthe method treats a disease associated with or mediated by a mutation ina gene transcript in a subject in need thereof comprising, administeringCompound (I) to the subject, wherein exon inclusion or exon exclusion ismodulated in one or more mature RNA isoforms produced from the genetranscript, wherein the disease is selected from Table 14 or 15.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, and wherein the subject is human, wherein thedisease is selected from Table 14 or 15.

Another aspect described herein is Compound (I) for use in the method,wherein the method treats a disease associated with or mediated by amutation in a gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, and wherein one or more of the mature RNAisoforms produce a functional protein, wherein the disease is selectedfrom Table 14 or 15.

Another aspect described herein is a pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell, andwherein the gene transcript is transcribed from a gene selected fromTable 14 or 15.

Another aspect described herein is Compound (I) for use in the method,wherein a gene having the mutated transcript is selected from Table 14or 15.

One aspect described herein is use of Compound (I) to treat a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof comprising, administering Compound (I) to thesubject, wherein exon inclusion or exon exclusion is modulated in one ormore mature RNA isoforms produced from the gene transcript, wherein thedisease is selected from Table 14 or 15.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript, andwherein the subject is human, wherein the disease is selected from Table14 or 15.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, administering Compound (I) tothe subject, wherein exon inclusion or exon exclusion is modulated inone or more mature RNA isoforms produced from the gene transcript, andwherein one or more of the mature RNA isoforms produce a functionalprotein, wherein the disease is selected from Table 14 or 15.

Another aspect described herein is use of Compound (I) to treat adisease associated with or mediated by a mutation in a gene transcriptin a subject in need thereof comprising, modulating the production ofone or more mature RNA isoforms from a gene transcript by administeringto the subject a pharmaceutical composition of Compound (I) and apharmaceutically acceptable carrier, excipient, or diluent, wherein exoninclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, and wherein the disease isselected from Table 14 or 15.

Another aspect described herein is a method for treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof comprising, administering Compound (I) to thesubject, wherein exon inclusion or exon exclusion is modulated in one ormore mature RNA isoforms produced from the gene transcript, wherein thesubject is human, and wherein the disease is selected from Table 14 or15.

Another aspect described herein is a method for treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof comprising, administering Compound (I) to thesubject, wherein exon inclusion or exon exclusion is modulated in one ormore mature RNA isoforms produced from the gene transcript, wherein oneor more of the mature RNA isoforms produce a functional protein, andwherein the disease is selected from Table 14 or 15.

Another aspect described herein is a method for treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof comprising, administering to the subject apharmaceutical composition of Compound (I) and a pharmaceuticallyacceptable carrier, excipient, or diluent, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, and wherein the disease is selected from Table14 or 15.

Table 14 lists diseases associated with genes having a mutatedtranscript identified by Clin VAR SpliceAI scores and the CNN Model, asdescribed herein, that are predicted to be modulated by Compound (I)toward either or both exon exclusion and exon inclusion.

TABLE 14 Gene Disease ABCA4 Stargardt disease 1 ABCC9 Hypertrichoticosteochondrodysplasia; Dilated cardiomyopathy 1O ACADSB Deficiency of2-methylbutyryl-CoA dehydrogenase ADAM10 Reticulate acropigmentation ofKitamura AGK Inborn genetic diseases; Sengers syndrome; Cataract,autosomal recessive congenital 5 ALDH3A2 Sjögren-Larsson syndrome ALMS1not provided ANTXR2 Hyaline fibromatosis syndrome APC Hereditarycancer-predisposing syndrome; Familial adenomatous polyposis 1 ARMC9Joubert Syndrome 30; ARMC9-related Joubert syndrome ASAH1 Farber diseaseASPM Microcephaly; Primary autosomal recessive microcephaly 5 ATMAtaxia-telangiectasia syndrome; Familial cancer of breast; Hereditarycancer-predisposing syndrome ATRX ATR-X syndrome BBS4 Bardet-Biedlsyndrome BFSP1 Cataract 33, multiple types BMPR2 Primary pulmonaryhypertension BRCA1 Hereditary breast and ovarian cancer syndrome;Hereditary cancer-predisposing syndrome; Breast-ovarian cancer, familial1 BRCA2 Tracheoesophageal fistula; Medulloblastoma; Malignant tumor ofprostate; Hereditary breast and ovarian cancer syndrome; Familial cancerof breast; Hereditary cancer-predisposing syndrome; Fanconi anemia,complementation group D1; Breast-ovarian cancer, familial 2; Breastand/or ovarian cancer; Glioma susceptibility 3; Pancreatic cancer 2;Wilms tumor 1 BRIP1 Hereditary cancer-predisposing syndrome; Familialcancer of breast; Fanconi anemia, complementation group J CA5A Carbonicanhydrase VA deficiency, hyperammonemia due to CAPN3 Muscle weakness;Muscular Diseases; Absent Achilles reflex CD3D Immunodeficiency 19 CDAN1Congenital dyserythropoietic anemia, type I CDH1 Hereditarycancer-predisposing syndrome CDH23 Usher syndrome, type 1D CERKLRetinitis pigmentosa; Retinitis pigmentosa 26 CFTR Inborn geneticdiseases; Cystic fibrosis; Hereditary pancreatitis CHD7 Inborn geneticdiseases CLCN1 Congenital myotonia, autosomal recessive form; Congenitalmyotonia, autosomal dominant form CLMP Intestinal pseudo-obstructionCLN3 Juvenile neuronal ceroid lipofuscinosis CNGB3 Achromatopsia 3 COG6Congenital disorder of glycosylation type 2L COL11A1 Connective tissuedisorder COL3A1 Ehlers-Danlos syndrome, type 4 COL4A3 Alport syndrome,autosomal recessive COL4A5 Alport syndrome 1, X-linked recessive COL5A2Ehlers-Danlos syndrome, classic type COL6A1 Bethlem myopathy 1 COL7A1Transient bullous dermolysis of the newborn CSTB Unverricht-Lundborgsyndrome CTNS Nephropathic cystinosis CTSK Pyknodysostosis CTU2Microcephaly, facial dysmorphism, renal agenesis, and ambiguousgenitalia syndrome CUBN Megaloblastic anemia due to inborn errors ofmetabolism CWC27 Retinitis pigmentosa with or without skeletal anomaliesCYBB Chronic granulomatous disease, X-linked DCX Heterotopia DGKEHemolytic-uremic syndrome DGUOK not provided DMD Becker musculardystrophy DNAH5 Ciliary dyskinesia DNAH9 Ciliary dyskinesia, primary, 40DYNC2H1 Jeune thoracic dystrophy; Short-rib thoracic dysplasia 3 with orwithout polydactyly DYNC2LI1 Short-rib thoracic dysplasia 15 withpolydactyly EBF3 Hypotonia, ataxia, and delayed development syndrome EBPChondrodysplasia punctata 2 X-linked dominant; MEND syndrome EP300Rubinstein-Taybi syndrome 2 ERCC6 Cockayne syndrome B F10 Factor Xdeficiency F13A1 Factor XIII subunit A deficiency F8 Hereditary factorVIII deficiency disease FBN1 Marfan syndrome; Cardiovascular phenotypeFIG4 Polymicrogyria, Amyotrophic lateral sclerosis 11,Charcot-Marie-Tooth disease, type 4J, Yunis-Varon syndrome FLT3 Acutemyeloid leukemia FUT8 Congenital disorder of glycosylation withdefective fucosylation 1 G6PC Glycogen storage disease type 1A GAAGlycogen storage disease, type II GABRG2 Rolandic epilepsy GCKMaturity-onset diabetes of the young, type 2 GLA Fabry disease; Fabrydisease, cardiac variant GNB5 Intellectual developmental disorder withcardiac arrhythmia GNPTAB Pseudo-Hurler polydystrophy; I cell disease;Mucolipidosis III alpha/beta, atypical GPR143 Ocular albinism, type IGPX4 Spondylometaphyseal dysplasia Sedaghatian type GRHPRNephrocalcinosis; Nephrolithiasis GRN Frontotemporal dementia GUCY2CMeconium ileus GYPA BLOOD GROUP ERIK HBB beta Thalassemia HFEHemochromatosis type 1 IDH1 Hepatocellular carcinoma; Medulloblastoma;Acute myeloid leukemia; Transitional cell carcinoma of the bladder;Multiple myeloma; Astrocytoma; Brainstem glioma; Lung adenocarcinoma;Neoplasm of brain; Neoplasm of the breast; Neoplasm of the largeintestine; Malignant melanoma of skin; Adenoid cystic carcinoma;Glioblastoma; Myelodysplastic syndrome; Adenocarcinoma of prostate IFT57Orofaciodigital Syndrome XVIII IL36RN Pustular psoriasis, generalizedKDSR Erythrokeratodermia variabilis et progressiva 4 KIAA0586 Short-ribthoracic dysplasia 14 with polydactyly KIAA1109 Alkuraya-KucinskasSyndrome KIF14 Microcephaly 20, primary, autosomal recessive KIT Partialalbinism KMT2D Kabuki syndrome 1 KRIT1 not provided LAMB3 Adultjunctional epidermolysis bullosa LDLR Familial hypercholesterolemiaLHCGR Leydig cell agenesis LIPA Lysosomal acid lipase deficiency LMNACardiovascular phenotype; Benign scapuloperoneal muscular dystrophy withcardiomyopathy MAPT Frontotemporal dementia MCFD2 Factor v and factorviii, combined deficiency of, 2 MLH1 Hereditary nonpolyposis coloncancer; Hereditary cancer-predisposing syndrome; Lynch syndrome MMABMethylmalonic aciduria cblB type MPC1 Mitochondrial pyruvate carrierdeficiency MSH2 Hereditary cancer-predisposing syndrome MTM1 SevereX-linked myotubular myopathy MYBPC3 Hypertrophic cardiomyopathy MYO7AUsher syndrome, type 1 NF1 Multiple cafe-au-lait spots; Hereditarycancer-predisposing syndrome; Neurofibromatosis, type 1 NIPBL Corneliade Lange syndrome 1 NPHP1 Nephronophthisis; Nephronophthisis 1 NR3C2Pseudohypoaldosteronism type 1 autosomal dominant NSD1Beckwith-Wiedemann syndrome OCA2 Tyrosinase-positive oculocutaneousalbinism OFD1 Oral-facial-digital syndrome OGT Mental retardation,X-Linked 106 ORC6 Meier-Gorlin syndrome 3 OTC not provided OTOGLDeafness, autosomal recessive 84b PAFAH1B1 Lissencephaly 1 PAHPhenylketonuria PARN Dyskeratosis congenita, autosomal recessive 6PDCD10 Cerebral cavernous malformations 3 PIGN Multiple congenitalanomalies- hypotonia-seizures syndrome 1 PMS2 Hereditary nonpolyposiscolon cancer; Hereditary cancer-predisposing syndrome; Lynch syndrome;Turcot syndrome POLG Seizures; Progressive sclerosing poliodystrophyPOMGNT1 Congenital muscular dystrophy- dystroglycanopathy with brain andeye anomalies, type A3; Muscle eye brain disease PPT1 Ceroidlipofuscinosis neuronal 1 PRMT7 Short stature, brachydactyly,intellectual developmental disability, and seizures PTEN Hereditarycancer-predisposing syndrome; PTEN hamartoma tumor syndrome; Cowdensyndrome 1 RAD51B Hereditary breast and ovarian cancer syndrome;Hereditary cancer-predisposing syndrome RAD51C Hereditarycancer-predisposing syndrome; Fanconi anemia, complementation group O;Breast-ovarian cancer, familial 3 RB1 Hereditary cancer-predisposingsyndrome; Retinoblastoma RHAG Rh-null, regulator type RNF216Hypogonadotropic hypogonadism 7 with or without anosmia; LeukodystrophyRTTN Congenital microcephaly; Microcephaly, short stature, andpolymicrogyria with or without seizures SCN1A Severe myoclonic epilepsyin infancy SCN5A Brugada syndrome 1 SDCCAG8 Senior-Loken syndrome 7 SDHDPheochromocytoma; Hereditary cancer- predisposing syndrome;Paraganglioma and gastric stromal sarcoma; Paragangliomas 1; Cowdensyndrome 3 SLC10A7 Short stature, amelogenesis imperfecta, and skeletaldysplasia with scoliosis SLC12A1 Bartter syndrome, type 1, antenatalSLC4A11 Corneal endothelial dystrophy SMS Snyder Robinson syndrome SNX10Osteopetrosis, autosomal recessive 8 SPAST Spastic paraplegia 4,autosomal dominant SPG11 Spastic paraplegia 11, autosomal recessiveSPTA1 Congenital hemolytic anemia; Hereditary pyropoikilocytosis;Spherocytosis type 3 SPTB Spherocytosis type 2 SRD5A2 3-Oxo-5alpha-steroid delta 4-dehydrogenase deficiency STK11 Peutz-Jegherssyndrome STXBP1 Inborn genetic diseases SYNGAP1 Mental retardation,autosomal dominant 5 TCIRG1 Osteopetrosis autosomal recessive 1 TECTANonsyndromic hearing loss and deafness TFR2 Hemochromatosis type 3TGFBR2 Loeys-Dietz syndrome 2 TJP2 Progressive familial intrahepaticcholestasis 4 TMEM138 Joubert syndrome 16 TMPRSS6 Microcytic anemia TP53Hereditary cancer-predisposing syndrome; Li-Fraumeni syndrome TPODeficiency of iodide peroxidase TRAPPC2 Spondyloepiphyseal dysplasiatarda TRIM37 Mulibrey nanism syndrome TYR Tyrosinase-negativeoculocutaneous albinism UROD Familial porphyria cutanea tarda VMA21Inborn genetic diseases; Myopathy, X-linked, with excessive autophagyVPS13B not provided WDR35 Short rib polydactyly syndrome 5 WDR73Galloway-Mowat syndrome 1 XPC Xeroderma pigmentosum, group C

Table 15 lists diseases associated with mutated genes that may bemodulated toward exon inclusion, as disclosed in InternationalPublication No. WO2016/115434.

TABLE 15 GeneBank Gene Gene Name Associated Diseases Acc. No. ARFGEF2ADP- Periventricular NG 011490.1 ribosylation heterotopia factor guaninewith microcephaly nucleotide- exchange factor 2 (brefeldin A-inhibited)ARHGEF6 RHO guanine Mental retardation, NG 008873.1 nucleotide X-linked46 exchange factor 6 CACNA1S Calcium Hypokalemic NG 009816.1 channel,periodic paralysis, voltage- type 1; Malignant dependent, hyperthermia LType, alpha- susceptibility 5; IS subunit Thyrotoxic periodic paralysis,susceptibility to, 1 CC2D2A Coiled-coil COACH syndrome; NG 013035.1 andC2 Joubert syndrome domain- 9; Meckel syndrome 6 containing protein 2ACDKL5 Cyclin- Angelman syndrome-like; NG 008475.1 dependent Epilepticencephalopathy, kinase-like 5 early infantile, 2 CHD2 ChromodomainEpileptic encephalopathy, NG 012826.1 helicase DNA- childhood-onsetbinding protein 2 CHD7 Chromodomain CHARGE syndrome; NG 007009.1helicase DNA- Hypogonadotropic binding protein 7 hypogonadism 5 with orwithout anosmia; Scoliosis, idiopathic 3 CHD8 Chromodomain Autism,susceptibility NG 021249.1 helicase DNA- binding protein 8 CHRNA4Cholinergic Epilepsy, nocturnal NG 011931.1 receptor, frontal lobe, 1;Nicotine neuronal addiction, susceptibility to nicotinic, alphapolypeptide 4 Cl9orfl2 Chromosome Spastic paraplegia 43, NG 031970.1 10open autosornal recessive; reading frame 12 Neurodegeneration with brainiron accumulation 4 COL6A3 Collagen type Bethlem myopathy; NG 008676.1VI, alpha-3 Ullrich congenital muscular dystrophy CUL4B Cullin 4b Mentalretardation, NG 009388.1 X-linked, syndromic 15 (Cabezas type) DEPDC5DEP domain- Epilepsy, familial focal, NG 034067.1 containing withvariable foci protein 5 DES Desmin Muscular dystrophy, NG 008043.1limb-girdle, type 2R; Cardiomyopathy, dilated, 11; Myopathy,myofibrillar, 1; Scapuloperoneal syndrome, neurogenic, Kaeser type DMDDystrophin Becker muscular NG 012232.1 dystrophy; Cardiomyopathy,dilated, 3B; Duchenne muscular dystrophy DNAJC6 DNAJ/HSP40 Parkinsondisease 19, NG 033843.1 homology juvenile-onset subfamily C member6DYNC2H1 Dynein, Short-rib thoracic NG 016423.1 cytoplasmic 2 dysplasia 3with or heavy chain 1 without polvdactvlv FBN1 Fibrillin 1 Acromicric NG008805.2 dysplasia; Aortic aneurysm, ascending, and dissection; Ectopialentis, familial; Marfan syndrome; MASS syndrome; Stiff skin syndrome;Weill-Marchesani syndrome 2, dominant FIG4 SAC domain- Polymicrogyria,bilateral NG 007977.1 containing temporooccipital, inositol Amyotrophiclateral phosphatase 3 sclerosis 11, Charcot-Marie-Tooth disease, type4J, Yunis-Varon syndrome FKTN Fukutin Cardiomyopathy, dilated, NG008754.1 IX; Muscular dystrophy- dystroglycanopathy (congenital withbrain and eye anomalies), type A4, B4 and C4 FMR1 Fragile X mentalFragile X syndrome; NG 007529.1 retardation Fragile X proteintremor/ataxia syndrome; Premature ovarian failure 1 GOSR2 Golgi SNAPEpilepsy, progressive NG 031806.1 receptor myoclonic 6 complex member 2GRIN2A Glutamate Epilepsy, focal, NG 011812.1 receptor, with speechdisorder ionotropic, and with or without N-methyl- mental retardationD-aspartate, subunit 2A HDAC8 Histone Cornelia de Lange NG 015851.1deacetylase 8 syndrome 5; Wilson-Turner svndrome IGHMBP2 Immunoglobin 2Charcot-Marie-Tooth NG 007976.1 MU-binding disease, axonal, type 2S;protein2 Neuronopathy, distal hereditary motor, type VI IKBKAP Inhibitorof Dysautonomia, familial NG 008788.1 kappa light polypeptide geneenhancer in B cells, kinase complex- associated protein KDM5CLysine-specific Mental retardation, NG 008085.1 demethylase 5C X-linked,syndromic, Claes-Jensen type LAMA2 Laminin alpha-2 Muscular dystrophy,NG 008678.1 congenital merosin-deficient; Muscular dystrophy,congenital, due to partial LAMA2 deficiency LRRK2 Leucine-rich Parkinsondisease 8 NG 011709.1 repeat kinase 2 LRSAM1 Leucine-richCharcot-Marie-Toothe NG 032008.1 repeat-and disease, axonal, type 2Psterile alpha motif- containing 1 MBD5 Methyl-CpG- Mental retardation,NG 017003.1 binding autosomal dominant 1 domain protein 5 MECP2Methyl-CpG- Angelman syndrome; NG 007107.2 binding Encephalopathy,protein 2 neonatal severe; Mental retardation, X-linked syndromic, Lubstype; Mental retardation, X-linked, syndromic 13; Rett syndrome; Rettsyndrome, preserved speech variant; Autism susceptibility, X-linked 3MICU1 Mitochondrial Myopathy with NG 033179.1 calcium extrapyramidalsigns uptake protein 1 MTM1 Myotubularin 1 Myotubular mvopathv, NG008199.1 X-linked NEB Nebulin Nemaline myopathy 2, NG 009382.2 autosomalrecessive OPHN1 Oligophreninl Mental retardation, NG 008960.1 X-linked,with cerebellar hypoplasia and distinctive facial appearance PGAP1Post-GPI Mental retardation, NC 000002.12 attachment to autosomal Range:proteins 1 recessive 42 196833004 19692 6995 PLEC Plectin Epidermolysisbullosa NG 012492.1 simplex with pyloric atresia; Epidermolysis bullosasimplex, Ogna type; Muscular dystrophy with epidermolysis bullosasimplex; Muscular dystrophy, limb-girdle, type 2Q RBI RetinoblastomaBladder cancer, NG 009009.1 1 somatic; Osteosarcoma, somatic;Retinoblastoma; Retinoblastoma, trilateral; Small cell cancer of thelung, somatic RYR1 Ryanodine Central core disease; NG 008866.1 receptor1 King-Denbo rough syndrome; Minicore myopathy with externalophthalmoplegia; Neuromuscular disease, congenital, with uniform type 1fiber; Malignant hyperthermia susceptibility 1 SBF2 SET-bindingCharcot-Marie-Tooth NG 008074.1 factor 2 disease, type 4B2 SCN9A Sodiumchannel, Epilepsy, generalized, NG 012798.1 voltage- with febrileseizures gated, type plus, type 7; IX, alpha subunit Erythermalgia,primary; Febrile seizures, familial, 3B; HSAN2D, autosomal recessive;Paroxysmal extreme pain disorder, Small fiber neuropathy; Dravetsyndrome, modifier of SCN1A Sodium channel, Dravet syndrome; NG 011906.1neuronal type 1, Epilepsy, generalized, alpha subunit with febrileseizures plus, type 2; Febrile seizures, familial, 3A; Migraine,familial hemiplegic, 3 SLC35A3 Solute carrier Arthrogryposis, mental NG033857.1 family 35 retardation, and seizures (UDP-N- acetylglucos- aminetransporter) member 3 SLC6A8 Solute carrier Cerebral creatine NG012016.1 family 6 deficiency syndrome 1 (neurotransmitter transportercreatine) member 8 SLC9A9 Solute carrier Autism susceptibility NG017077.1 family 9 (sodium/ hydrogen exchanger) member 9 SMCHD1Structural Fascioscapulohumer al NG 031972.1 maintenance of muscularchromosomes dystrophy 2, digenic flexible hinge domain- containingprotein 1 STXBP1 Syntaxin-binding Epileptic encephalopathy, NG 016623.1protein 1 early infantile, 4 SYNGAP1 Synaptic RAS- Mental retardation,NG 016137.1 GTPase- autosomal dominant 5 activating protein 1 SZT2Seizure Epileptic encephalopathy, NG 029091.1 threshold 2 earlyinfantile, 18 TSC2 Tuberin Lymphangioleiomyo NG 005895.1 matosis,somatic; Tuberous sclerosis-2 TSC1 Hamartin Focal cortical dysplasia, NG012386.1 Taylor balloon cell type; Lymphangioleiomyo matosis; Tuberoussclerosis-I WDR45 WD40 repeat- Neurodegeneration with NG 033004.1containing brain iron accumulation 5 protein 45

Another aspect provided herein is a disease associated with or mediatedby a mutation in a gene, wherein the disease is selected from Table 14or 15.

Another aspect provided herein is a disease associated with or mediatedby a mutation in a gene, wherein the disease is selected from Table 14.

Another aspect provided herein is a disease associated with or mediatedby a mutation in a gene, wherein the disease is selected from Table 15.

Another aspect provided herein is a disease associated with or mediatedby a mutation in a gene, wherein the disease is other than a diseaseselected from Table 14 or 15.

Another aspect provided herein is a disease associated with or mediatedby a mutation in a gene, wherein the disease is other than a diseaseselected from Table 14.

Another aspect provided herein is a disease associated with or mediatedby a mutation in a gene, wherein the disease is other than a diseaseselected from Table 15.

Another aspect provided herein is a disease associated with or mediatedby a mutation in a gene, wherein the disease is selected from the groupconsisting of: 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency,Absent Achilles reflex, Achromatopsia 3, Acute myeloid leukemia,Adenocarcinoma of prostate, Adenoid cystic carcinoma, Adult junctionalepidermolysis bullosa, Alkuraya-kucinskas syndrome, Alport syndrome(Autosomal recessive), Alport syndrome 1 (X-linked recessive), Ambiguousgenitalia syndrome, Amelogenesis imperfecta (Short stature and skeletaldysplasia with scoliosis), Amyotrophic lateral sclerosis, Astrocytoma,Ataxia, Ataxia-telangiectasia syndrome, ATR-X syndrome, Autism spectrumdisorders, Autism, Bardet-Biedl syndrome, Bartter syndrome (Type 1,antenatal), Becker muscular dystrophy, Beckwith-Wiedemann syndrome,Benign scapuloperoneal muscular dystrophy with cardiomyopathy, Betathalassemia, Bethlem myopathy 1, Blood group ERIK, Brainstem glioma,Breast cancer (familial), Breast-ovarian cancer (familial 1),Breast-ovarian cancer (familial 2), Breast-ovarian cancer (Familial 3),Breast-ovarian cancer, Brugada syndrome 1, Carbonic anhydrase VAdeficiency (hyperammonemia due to), Cardiovascular phenotype, Cataract(autosomal recessive congenital 5), Cataract 33 (multiple types),Cerebral cavernous malformations 3, Ceroid lipofuscinosis neuronal 1,Charcot-Marie-Tooth disease, CHARGE syndrome, Chondrodysplasia punctata2 (X-linked dominant), Chronic granulomatous disease (X-linked), Ciliarydyskinesia (Primary 40), Ciliary dyskinesia, Cockayne syndrome B,Congenital disorder of glycosylation (Type 2L), Congenital disorder ofglycosylation with defective fucosylation, Congenital dyserythropoieticanemia (Type I), Congenital hemolytic anemia, Congenital microcephaly,Congenital muscular dystrophy-dystroglycanopathy with brain and eyeanomalies (Type A3), Congenital myotonia (Autosomal dominant form),Congenital myotonia (Autosomal recessive form), Connective tissuedisorder, Corneal endothelial dystrophy, Cornelia de Lange syndrome 1,Cowden syndrome 1, Cowden syndrome 3, Cystic fibrosis (Atypical), Cysticfibrosis, Deafness (Autosomal recessive 84b), Deficiency of2-methylbutyryl-CoA dehydrogenase, Deficiency of iodide peroxidase,Delayed development syndrome, Dementia, Dilated cardiomyopathy 10,Dyskeratosis congenita (Autosomal recessive 6), Ehlers-Danlos syndrome(Classic type), Ehlers-Danlos syndrome (Type 4), Epilepsy, Epilepticencephalopathy, Erythrokeratodermia variabilis et progressiva 4, Fabrydisease (Cardiac variant), Fabry disease, Facial dysmorphism, Factor vand Factor viii (combined deficiency of, 2), Factor X deficiency, FactorXIII subunit A deficiency, Familial adenomatous polyposis 1, Familialcancer of breast, Familial dysautonomia, Familial hypercholesterolemia,Familial isolated growth hormone deficiency type II, Familial porphyriacutanea tarda, Fanconi anemia (complementation group D1), Fanconi anemia(complementation group J), Fanconi anemia (Complementation group O),Farber disease, Frasier syndrome, Frontotemporal dementia,Galloway-Mowat syndrome 1, Glioblastoma, Glioma susceptibility 3,Glycogen storage disease (Type 1A), Glycogen storage disease (Type II),Hemochromatosis (Type 1), Hemochromatosis (Type 3), Hemolytic-uremicsyndrome, Hepatocellular carcinoma, Hereditary breast and ovarian cancersyndrome, Hereditary cancer-predisposing syndrome, Hereditary factorVIII deficiency disease, Hereditary nonpolyposis colon cancer,Hereditary pancreatitis, Hereditary pyropoikilocytosis, Heterotopia,Huntington's disease, Hyaline fibromatosis syndrome, Hypertrichoticosteochondrodysplasia, Hypertrophic cardiomyopathy, Hypogonadotropichypogonadism 7 with anosmia, Hypogonadotropic hypogonadism 7 withoutanosmia, Hypotonia, I cell disease, Immunodeficiency 19, Inborn geneticdiseases, Intellectual developmental disability (with short stature,brachydactyly and seizures), Intellectual developmental disorder(Cardiac arrhythmia), Intestinal pseudo-obstruction, Jeune thoracicdystrophy, Joubert syndrome (Armc9-related), Joubert syndrome 16,Joubert syndrome 30, Juvenile neuronal ceroid lipofuscinosis, Kabukisyndrome 1, Leukodystrophy, Leydig cell agenesis, Li-Fraumeni syndrome,Lissencephaly 1, Loeys-Dietz syndrome 2, Lung adenocarcinoma, Lynchsyndrome, Lysosomal acid lipase deficiency, Malignant melanoma of skin,Malignant tumor of prostate, Marfan syndrome (Cardiovascular phenotype),Marfan syndrome, Maturity-onset diabetes of the young (Type 2), Meconiumileus, Medulloblastoma, Megaloblastic anemia due to inborn errors ofmetabolism, Meier-Gorlin syndrome 3, MEND syndrome, Menkes disease,Mental retardation (Autosomal dominant 5), Mental retardation (X-linked106), Methylmalonic aciduria (cblB type), Microcephaly (short stature),Microcephaly 20 (Primary, autosomal recessive), Microcephaly 5 (Primaryautosomal recessive), Microcephaly, Microcytic anemia, MitochondrialDNA-depletion syndrome 3, Mitochondrial pyruvate carrier deficiency,Mucolipidosis III alpha/beta (Atypical), Mulibrey nanism syndrome,Multiple cafe-au-lait spots, Multiple congenitalanomalies-hypotonia-seizures syndrome 1, Multiple myeloma, Muscle eyebrain disease, Muscle weakness, Muscular diseases, Muscular dystrophies,Myelodysplastic syndrome, Myopathies, Myopathy (X-linked, with excessiveautophagy) Myotonic dystrophy (Type 1), Myotonic dystrophy (Type 2),Neoplasm of the brain, Neoplasm of the breast, Neoplasm of the largeintestine, Nephrocalcinosis, Nephrolithiasis, Nephronophthisis 1,Nephronophthisis, Nephropathic cystinosis, Neurofibromatosis(Peripheral), Neurofibromatosis (Type 1), Neurofibromatosis (VonRecklinghausen), Nonsyndromic hearing loss and deafness, Occipital hornsyndrome, Ocular albinism (Type I), Oral-facial-digital syndrome,Orofaciodigital syndrome XVIII, Osteopetrosis (Autosomal recessive 8),Osteopetrosis (Autosomal recessive 1), Ovarian cancer, Pancreatic cancer2, Paraganglioma and gastric stromal sarcoma, Paragangliomas 1,Parkinson's disease linked to Chromosome 17, Parkinson's disease,Partial albinism, Peutz-Jeghers syndrome, Phenylketonuria,Pheochromocytoma, Polymicrogyria with seizures, Polymicrogyria withoutseizures, Primary pulmonary hypertension, Progressive familialintrahepatic cholestasis 4, Progressive sclerosing poliodystrophy,Pseudo-Hurler polydystrophy, Pseudohypoaldosteronism type 1 (Autosomaldominant), PTEN hamartoma tumor syndrome, Pustular psoriasis(Generalized), Pyknodysostosis, Renal agenesis, Reticulateacropigmentation of Kitamura, Retinitis pigmentosa 26, Retinitispigmentosa with skeletal anomalies, Retinitis pigmentosa withoutskeletal anomalies, Retinitis pigmentosa, Retinoblastoma, Rh-null(Regulator type), Rolandic epilepsy, Rubinstein-Taybi syndrome 2,Schizophrenia, Seizures, Sengers syndrome, Senior-Loken syndrome 7,Severe myoclonic epilepsy (Infancy), Severe X-linked myotubularmyopathy, Short rib polydactyly syndrome 5, Short-rib thoracic dysplasia14 with polydactyly, Short-rib thoracic dysplasia 15 with polydactyly,Short-rib thoracic dysplasia 3 with polydactyly, Short-rib thoracicdysplasia 3 without polydactyly, Sj√∂gren-Larsson syndrome, SnyderRobinson syndrome, Spastic paraplegia 11 (Autosomal recessive), Spasticparaplegia 4 (Autosomal dominant), Spherocytosis type 2, Spherocytosistype 3, Spondyloepiphyseal dysplasia tarda, Spondylometaphysealdysplasia (Sedaghatian type), Stargardt disease 1, Tracheoesophagealfistula, Transient bullous dermolysis of the newborn, Transitional cellcarcinoma of the bladder, Tuberous sclerosis, Turcot syndrome,Tyrosinase-negative oculocutaneous albinism, Tyrosinase-positiveoculocutaneous albinism, Unverricht-Lundborg syndrome, Usher syndrome(Type 1), Usher syndrome (Type 1D), Wilms tumor 1, and Xerodermapigmentosum (Group C), and wherein the gene is selected from Tables 1,2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect provided herein is a disease associated with or mediatedby a mutation in a gene, wherein the disease is selected from: Autism,Blood group ERIK, Breast cancer, Ovarian cancer, Dementia, Epilepsy,Mental retardation, Muscular dystrophies, Myopathies, Neurofibromatosis1, Parkinson's disease, or Schizophrenia, and wherein the gene isselected from Tables 1, 2, 3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect provided herein is a disease associated with or mediatedby a mutation in a gene, wherein the disease is selected from: 3-Oxo-5alpha-steroid delta 4-dehydrogenase deficiency, Amyotrophic lateralsclerosis, Ataxia-telangiectasia syndrome, Atypical cystic fibrosis,Autism, Autism spectrum disorders, Beckwith-Wiedemann syndrome, Betathalassemia, Blood group ERIK, Breast cancer, Ovarian cancer, Carbonicanhydrase VA deficiency, Charcot-Marie-Tooth disease, CHARGE syndrome,Ciliary dyskinesia, Congenital hemolytic anemia, Deficiency of iodideperoxidase, Dementia, Dyskeratosis congenita, Epilepsy, Epilepticencephalopathy, Fabry disease, Familial dysautonomia, Familial isolatedgrowth hormone deficiency type II, Frasier syndrome, Frontotemporaldementia, Huntington's disease, Lysosomal acid lipase deficiency, Marfansyndrome, Meier-Gorlin syndrome 3, Menkes Disease, Mental retardation,Mitochondrial DNA-depletion syndrome 3, Multiple congenitalanomalies-hypotonia-seizures syndrome 1, Muscular dystrophies,Myopathies, Myotonic dystrophy type 1, Myotonic dystrophy type 2,Neurofibromatosis 1, Neurofibromatosis (Peripheral), Neurofibromatosis(Von Recklinghausen), Occipital horn syndrome, Osteopetrosis autosomalrecessive 1, Parkinson's disease, Parkinson's linked to Chromosome 17,Progressive sclerosing poliodystrophy, Pustular psoriasis,Retinoblastoma, Schizophrenia, Spondylometaphyseal dysplasia, orTuberous sclerosis, and wherein the gene is selected from Tables 1, 2,3, 4, 5, 6, 7, 8, 9a, 10, 11, 12 or 13.

Another aspect provided herein is a disease associated with or mediatedby a mutation in a gene, wherein the disease is selected from: 3-Oxo-5alpha-steroid delta 4-dehydrogenase deficiency, Amyotrophic lateralsclerosis, Ataxia-telangiectasia syndrome, Atypical cystic fibrosis,Autism spectrum disorders, Beckwith-Wiedemann syndrome, Betathalassemia, Carbonic anhydrase VA deficiency, Charcot-Marie-Toothdisease, CHARGE syndrome, Ciliary dyskinesia, Congenital hemolyticanemia, Deficiency of iodide peroxidase, Dyskeratosis congenita,Epileptic encephalopathy, Fabry disease, Familial dysautonomia, Familialisolated growth hormone deficiency type II, Frasier syndrome,Frontotemporal dementia, Huntington's disease, Lysosomal acid lipasedeficiency, Marfan syndrome, Meier-Gorlin syndrome 3, Menkes Disease,Mitochondrial DNA-depletion syndrome 3, Multiple congenitalanomalies-hypotonia-seizures syndrome 1, Myotonic dystrophy type 1,Myotonic dystrophy type 2, Neurofibromatosis (Peripheral),Neurofibromatosis (Von Recklinghausen), Occipital horn syndrome,Osteopetrosis autosomal recessive 1, Parkinson's linked to Chromosome17, Progressive sclerosing poliodystrophy, Pustular psoriasis,Retinoblastoma, Spondylometaphyseal dysplasia, or Tuberous sclerosis.

Another aspect provided herein is a disease associated with or mediatedby a mutation in a gene, wherein the disease is selected from Table 14or 15.

Another aspect provided herein is a disease associated with or mediatedby a mutation in a gene, wherein the disease is selected from Table 14.

Another aspect provided herein is a disease associated with or mediatedby a mutation in a gene, wherein the disease is other than a diseaseselected from Table 14.

Another aspect provided herein is a disease associated with or mediatedby a mutation in a gene, wherein the disease is selected from Table 15.

Another aspect provided herein is a disease associated with or mediatedby a mutation in a gene, wherein the disease is other than a diseaseselected from Table 15.

In Vitro and In Vivo Assays of RNA Transcripts

In one aspect, the cell(s) contacted or cultured with Compound (I) isfrom a cell line. In another aspect, the cell(s) contacted or culturedwith Compound (I) is a cell line derived from a subject with a disease(e.g., a disease identified herein). In another aspect, the cell(s)contacted or cultured with Compound (I) is from a cell line known tohave aberrant RNA transcript levels transcribed from a particulargene(s). In another aspect, the cell(s) contacted or cultured withCompound (I) is from a cell line derived from a subject with a diseaseknown to have aberrant RNA transcript levels transcribed from aparticular gene(s). In another aspect, the cell(s) contacted or culturedwith Compound (I) is a cancer cell line. In another aspect, the cell(s)contacted or cultured with Compound (I) is from a cell line derived froma subject with a disease known to have an aberrant amount of an RNAisoform(s) transcribed from a particular gene(s), an aberrant amount ofa protein isoform(s) produced from the particular gene(s), or both.Non-limiting examples of cell lines include 293, 3T3, 4T1, 721, 9L,A2780, A172, A20, A253, A431, A-549, ALC, B16, B35, BCP-1, BEAS-2B,bEnd.3, BHK, BR 293, BT20, BT483, BxPC3, C2C12, C3H-10T1/2, C6/36, C6,Cal-27, CHO, COR-L23, COS, COV-434, CML T1, CMT, CRL7030, CT26, D17,DH82, DU145, DuCaP, EL4, EM2, EM3, EMT6, FM3, H1299, H69, H1B54, H1B55,HCA2, HEK-293, HeLa, Hepalclc7, HL-60, HMEC, Hs578T, HsS78Bst, HT-29,HTB2, HUVEC, Jurkat, J558L, JY, K562, Ku812, KCL22, KG1, KYO1, LNCap,Ma-Mel, MC-38, MCF-7, MCF-10A, MDA-MB-231, MDA-MB-468, MDA-MB-435, MDCK,MG63, MOR/0.2R, MONO-MAC 6, MRC5, MTD-1A, NCI-H69, NIH-3T3, NALM-1, NSO,NW-145, OPCN, OPCT, PNT-1A, PNT-2, Raji, RBL, RenCa, RIN-5F, RMA,Saos-2, Sf21, Sf9, SiHa, SKBR3, SKOV-3, T2, T-47D, T84, THP1, U373, U87,U937, VCaP, Vero, VERY, W138, WM39, WT-49, X63, YAC-1, and YAR cells. Inanother aspect, the cells are fibroblasts differentiated from PSC(pluripotent stem cells). In another aspect, the cells are humanfibroblasts. In another aspect, the cells are from a patient.

In another aspect, provided herein is a method for determining whetherCompound (I) modulates the amount of an RNA transcript (e.g., an mRNAtranscript), comprising: (a) contacting a cell or tissue sample withCompound (I); and (b) determining the amount of the RNA transcriptproduced by the tissue sample, wherein an alteration in the amount ofthe RNA transcript in the presence of the compound relative to theamount of the RNA transcript in the absence of the compound or thepresence of a negative control (e.g., a vehicle control such as PBS orDMSO) indicates that Compound (I) modulates the amount of the RNAtranscript.

In another aspect, provided herein is a method for determining whetherCompound (I) modulates the amount of an RNA transcript (e.g., an mRNAtranscript), comprising: (a) contacting a first cell or a first tissuesample with Compound (I), (b) contacting a second cell or a secondtissue sample with a negative control (e.g., a vehicle control, such asPBS or DMSO); and (c) determining the amount of the RNA transcriptproduced by the first cell or first tissue sample and the second cell orsecond tissue sample; and (d) comparing the amount of the RNA transcriptproduced by the first cell or first tissue sample to the amount of theRNA transcript produced by the second cell or second tissue sample,wherein an alteration in the amount of the RNA transcript produced bythe first cell or first tissue sample relative to the amount of the RNAtranscript produced by the second cell or second tissue sample indicatesthat Compound (I) modulates the amount of the RNA transcript. Any tissuesample containing cells may be used in the accordance with thesemethods. In another aspect, the tissue sample is a blood sample, a skinsample, a muscle sample, or a tumor sample. Techniques known to oneskilled in the art may be used to obtain a tissue sample from a subject.

In another aspect, a dose-response assay is performed. In anotheraspect, the dose response assay comprises: (a) contacting a cell(s) witha concentration of Compound (I); (b) determining the amount of the RNAtranscript produced by the cell(s), wherein an alteration in the amountof the RNA transcript in the presence of the compound relative to theamount of the RNA transcript in the absence of the compound or thepresence of a negative control (e.g., a vehicle control such as PBS orDMSO) indicates that Compound (I) modulates the amount of the RNAtranscript; (c) repeating steps (a) and (b), wherein the onlyexperimental variable changed is the concentration of the compound; and(d) comparing the amount of the RNA transcript produced at the differentconcentrations of the compound. In another aspect, the dose responseassay comprises: (a) culturing a cell(s) in the presence of Compound(I), (b) isolating the RNA transcript from the cell(s) after a certainperiod of time; (c) determining the amount of the RNA transcriptproduced by the cell(s), wherein an alteration in the amount of the RNAtranscript in the presence of the compound relative to the amount of theRNA transcript in the absence of the compound or the presence of anegative control (e.g., a vehicle control such as PBS or DMSO) indicatesthat Compound (I) modulates the amount of the RNA transcript; (d)repeating steps (a), (b), and (c), wherein the only experimentalvariable changed is the concentration of the compound; and (e) comparingthe amount of the RNA transcript produced at the differentconcentrations of the compound. In another aspect, the dose-responseassay comprises: (a) contacting each well of a microtiter platecontaining cells with a different concentration of Compound (I); (b)determining the amount of an RNA transcript produced by cells in eachwell; and (c) assessing the change of the amount of the RNA transcriptat the different concentrations of the compound or form thereof.

In another aspect, the dose response assay comprises: (a) contactingcells with a concentration of Compound (I), wherein the cells are withinthe wells of a tissue culture container (e.g., a 96-well plate) at aboutthe same density within each well, and wherein the cells are contactedwith different concentrations of Compound (I) in different wells; (b)isolating the RNA from said cells in each well; (c) determining theamount of the RNA transcript produced by the cell(s) in each well; and(d) assessing change in the amount of the RNA transcript in the presenceof one or more concentrations of compound relative to the amount of theRNA transcript in the presence of a different concentration of thecompound or the absence of Compound (I) or the presence of a negativecontrol (e.g., a vehicle control such as PBS or DMSO).

In another aspect, contacting of the cell(s) with the compound occurs incell culture. In another aspect, contacting of the cell(s) with thecompound occurs in a subject, such as a non-human animal subject.

In another aspect described herein, the cell(s) is contacted or culturedwith Compound (I), or a tissue sample is contacted with Compound (I), ora negative control for a period of 15 minutes, 30 minutes, 45 minutes, 1hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 18hours, 24 hours, 48 hours, 72 hours or more. In another aspect describedherein, the cell(s) is contacted or cultured with Compound (I), or atissue sample is contacted with Compound (I), or a negative control fora period of 15 minutes to 1 hour, 1 to 2 hours, 2 to 4 hours, 6 to 12hours, 12 to 18 hours, 12 to 24 hours, 28 to 24 hours, 24 to 48 hours,48 to 72 hours.

In another aspect described herein, the cell(s) is contacted or culturedwith a certain concentration of Compound (I), or a tissue sample iscontacted with a certain concentration of Compound (I), wherein thecertain concentration is 0.01 μM, 0.05 μM, 1 μM, 2 μM, 5 μM, 10 μM, 15μM, 20 μM, 25 μM, 50 μM, 60 μM, 75 μM, 100 μM, or 150 μM. In one aspectdescribed herein, the cell(s) is contacted or cultured with certainconcentration of Compound (I), or a tissue sample is contacted with acertain concentration of Compound (I), wherein the certain concentrationis 175 μM, 200 μM, 250 μM, 275 μM, 300 μM, 350 μM, 400 μM, 450 μM, 500μM, 550 μM 600 μM, 650 μM, 700 μM, 750 μM, 800 μM, 850 μM, 900 μM, 950μM or 1 mM. In another aspect described herein, the cell(s) is contactedor cultured with certain concentration of Compound (I), or a tissuesample is contacted with a certain concentration of Compound (I),wherein the certain concentration is 5 nM, 10 nM, 20 nM, 30 nM, 40 nM,50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 150 nM, 200 nM, 250 nM, 300nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750nM, 800 nM, 850 nM, 900 nM, or 950 nM. In another aspect describedherein, the cell(s) is contacted or cultured with certain concentrationof Compound (I), or a tissue sample is contacted with a certainconcentration of Compound (I), wherein the certain concentration isbetween 0.01 μM to 0.1 μM, 0.1 μM to 1 μM, 1 μM to 50 μM, 50 μM to 100μM, 100 μM to 500 μM, 500 μM to 1 nM, 1 nM to 10 nM, 10 nM to 50 nM, 50nM to 100 nM, 100 nM to 500 nM, 500 nM to 1000 nM.

In another aspect, provided herein is a method for determining whetherCompound (I) modulates the amount of an RNA transcript (e.g., an mRNAtranscript), comprising: (a) administering Compound (I) to a subject (inanother aspect, a non-human animal); and (b) determining the amount ofthe RNA transcript in a sample obtained from the subject, wherein analteration in the amount of the RNA transcript measured in the samplefrom the subject administered the compound or form thereof relative tothe amount of the RNA transcript in a sample from the subject prior toadministration of the compound or form thereof or a sample from adifferent subject from the same species not administered the compound orform thereof indicates that Compound (I) modulates the amount of the RNAtranscript. In another aspect, provided herein is a method fordetermining whether Compound (I) modulates the amount of an RNAtranscript (e.g., an mRNA transcript), comprising: (a) administeringCompound (I) to a first subject (in another aspect, a non-human animal);(b) administering a negative control (e.g., a pharmaceutical carrier) toa second subject (in another aspect, a non-human animal) of the samespecies as the first subject; and (c) determining the amount of the RNAtranscript in a first tissue sample from the first subject and theamount of the RNA transcript in the second tissue sample from the secondsubject; and (d) comparing the amount of the RNA transcript in the firsttissue sample to the amount of the RNA transcript in the second tissuesample, wherein an alteration in the amount of the RNA transcript in thefirst tissue sample relative to the amount of the RNA transcript in thesecond tissue sample indicates that Compound (I) modulates the amount ofthe RNA transcript.

In another aspect, Compound (I) or form thereof is administered to asubject at a dose of about 0.001 mg/kg/day to about 500 mg/kg/day. Inanother aspect, a single dose of Compound (I) is administered to asubject in accordance with the methods described herein. In anotheraspect, 2, 3, 4, 5 or more doses of Compound (I) is administered to asubject in accordance with the methods described herein. In anotheraspect, Compound (I) is administered in a subject in a pharmaceuticallyacceptable carrier, excipient or diluent.

In another aspect, provided herein is a method for determining whetherCompound (I) modulates the splicing of an RNA transcript (e.g., an mRNAtranscript), comprising: (a) administering Compound (I) to a subject (inanother aspect, a non-human animal); and (b) determining the amount oftwo or more RNA transcript splice variants in a sample obtained from thesubject, wherein an alteration in the amount of the two or more RNAtranscript splice variants measured in the sample from the subjectadministered the compound or form thereof relative to the amount of thetwo or more RNA transcript splice variants in a sample from the subjectprior to administration of the compound or form thereof or a sample froma different subject from the same species not administered the compoundor form thereof indicates that Compound (I) modulates the splicing ofthe RNA transcript. In another aspect, provided herein is a method fordetermining whether Compound (I) modulates the splicing of an RNAtranscript (e.g., an mRNA transcript), comprising: (a) administeringCompound (I) to a first subject (in another aspect, a non-human animal);(b) administering a negative control (e.g., a pharmaceutical carrier) toa second subject (in another aspect, a non-human animal) of the samespecies as the first subject; and (c) determining the amount of two ormore RNA transcript splice variants in a first tissue sample from thefirst subject and the amount of two or more RNA transcript splicevariants in the second tissue sample from the second subject; and (d)comparing the amount of the two or more RNA transcript splice variantsin the first tissue sample to the amount of the two or more RNAtranscript splice variants in the second tissue sample, wherein analteration in the amount of the two or more RNA transcript splicevariants in the first tissue sample relative to the amount of the two ormore RNA transcript splice variants in the second tissue sampleindicates that Compound (I) modulates the splicing of the RNAtranscript. In another aspect, Compound (I) or form thereof isadministered to a subject at a dose of about 0.001 mg/kg/day to about500 mg/kg/day. In another aspect, a single dose of Compound (I) isadministered to a subject in accordance with the methods describedherein. In another aspect, 2, 3, 4, 5 or more doses of Compound (I) isadministered to a subject in accordance with the methods describedherein. In another aspect, Compound (I) is administered in a subject ina pharmaceutically acceptable carrier, excipient or diluent. In anotheraspect, Compound (I) that is contacted or cultured with a cell(s) or atissue sample or administered to a subject is a compound describedherein.

Techniques known to one skilled in the art may be used to determine theamount of an RNA transcript(s). In one aspect, the amount of one, two,three or more RNA transcripts is measured using deep sequencing, such asILLUMIINA® RNASeq, ILLUMIINA® next generation sequencing (NGS), IONTORRENT™ RNA next generation sequencing, 454™ pyrosequencing, orSequencing by Oligo Ligation Detection (SOLID™). In another aspect, theamount of RNA transcripts is measured using an exon array, such as theGENECHIP® human exon array. In another aspect, the amount of one, two,three or more RNA transcripts is determined by RT-PCR. In anotheraspect, the amount of one, two, three or more RNA transcripts ismeasured by RT-qPCR. Techniques for conducting these assays are known toone skilled in the art.

In another aspect, the stability of one or more RNA transcripts isdetermined by serial analysis of gene expression (SAGE), differentialdisplay analysis (DD), RNA arbitrarily primer (RAP)-PCR, restrictionendonuclease-lytic analysis of differentially expressed sequences(READS), amplified restriction fragment-length polymorphism (ALFP),total gene expression analysis (TOGA), RT-PCR, RT-qPCR, high-densitycDNA filter hybridization analysis (HDFCA), suppression subtractivehybridization (SSH), differential screening (DS), cDNA arrays,oligonucleotide chips, or tissue microarrays. In another aspect, thestability of one or more RNA transcripts is determined by Northernblots, RNase protection, or slot blots.

In another aspect, the transcription in a cell(s) or tissue sample isinhibited before (e.g., 5 minutes, 10 minutes, 30 minutes, 1 hour, 2hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36hours, 48 hours, or 72 hours before) or after (e.g., 5 minutes, 10minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12hours, 18 hours, 24 hours, 36 hours, 48 hours, or 72 hours after) thecell or the tissue sample is contacted or cultured with an inhibitor oftranscription, such as α-amanitin, DRB, flavopiridol, triptolide, oractinomycin-D. In another aspect, the transcription in a cell(s) ortissue sample is inhibited with an inhibitor of transcription, such asα-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D, while thecell(s) or tissue sample is contacted or cultured with Compound (I).

In another aspect, the level of transcription of one or more RNAtranscripts is determined by nuclear run-on assay or an in vitrotranscription initiation and elongation assay. In another aspect, thedetection of transcription is based on measuring radioactivity orfluorescence. In another aspect, a PCR-based amplification step is used.

In one aspect, the amount of alternatively spliced forms of the RNAtranscripts of a particular gene are measured to see if there is analteration in the amount of one, two or more alternatively spliced formsof the RNA transcripts of the gene. In another aspect, the amount of anisoform(s) encoded by a particular gene is measured to see if there isan alteration in the amount of the isoform(s). In another aspect, thelevels of spliced forms of RNA are quantified by RT-PCR, RT-qPCR, ornorthern blotting. In another aspect, sequence-specific techniques maybe used to detect the levels of an individual spliceoform. In anotheraspect, splicing is measured in vitro using nuclear extracts. In anotheraspect, detection is based on measuring radioactivity or fluorescence.Techniques known to one skilled in the art may be used to measurealterations in the amount of alternatively spliced forms of an RNAtranscript of a gene and alterations in the amount of an isoform encodedby a gene.

Modulating Isoform Splicing

In some aspects, analysis is performed on data derived from the assay tomeasure the magnitude of splicing to determine the amount of exonsspliced into an mRNA transcript that is produced in the presence ofCompound (I) relative to the amount in the absence of Compound (I) orpresence of a negative control. In a preferred aspect, the methodutilized is calculation of change in Percent Spliced In (ΔPSI). Themethod utilizes read data from RNAseq (or any other method that candistinguish mRNA splice isoforms) to calculate the ratio (percentage)between reads that either demonstrate inclusion (junctions between theupstream exon and the exon of interest) or exclusion (junction betweenthe upstream and downstream exons, excluding the exon of interest), todemonstrate whether the presence of Compound (I) affects the amount ofexon inclusion relative to the amount of inclusion in the absence ofCompound (I) or the presence of a negative control. The ΔPSI value isderived from the formula:

ΔPSI (%)=(C−U)×100

Where “U” represents the Percent Spliced In value for splicing to occurin the absence of Compound (I):

U=(a+b)/2/[(a+b)/2+c]

Where “C” represents the Percent Spliced In value for splicing to occurin the presence of Compound (I).

C=(a+b)/2/[(a+b)/2+c]

The values for “a” and “b” represent the number of reads supporting theprobability for potential inclusion or exclusion of an exon in an RNAtranscript. The “a” value is derived from the number of reads within anexon triplet covering, in 5′ to 3′ order: the last few bases (>1nucleotide) of an upstream exon operably linked to the first few bases(>1 nucleotide) of a middle exon. The “b” value is derived from thenumber of reads within an exon triplet covering, in 5′ to 3′ order: thelast few bases (>1 nucleotide) of the middle exon operably linked to thefirst few bases (>1 nucleotide) of a downstream exon. The number ofreads will indicate whether the splice junction of a middle exon hasbeen identified as potentially having a CNN Motif(s) by the CNN Modeldescribed herein, wherein the inclusion or exclusion of the middle exonmay be modulated in the presence of Compound (I) to produce one or moremature RNA isoforms from the gene transcript. The value for “c”represents the number of reads supporting the exclusion of the middleexon.

Accordingly, an alteration in the CNN Motifs may affect the splicingtoward one Class or another (inclusion or exclusion) of the middle exonin the presence of Compound (I), thus making the PSI value for “C” inthe presence of Compound (I) different from the PSI value for “U” in theabsence of Compound (I). The statistically significant value for theprobability of inclusion or exclusion may be obtained according tostatistical or probability analysis methods known to those of ordinaryskill in the art.

In some aspects, a statistical analysis or other probability analysis isperformed on data from the assay utilized to measure an RNA transcript.In certain aspects, for example, a Fisher's Exact Test statisticalanalysis is performed by comparing the total number of reads for theinclusion and exclusion of a middle exon based on data from one or moreassays used to measure whether the amount of an RNA transcript ismodulated in the presence of Compound (I) relative to the amount in theabsence of Compound (I) or presence of a negative control. In specificaspects, the statistical analysis results in a confidence value forthose modulated RNA transcripts of 10%, 5%, 4%, 3%, 2%, %, 0.5%, 0.1%,0.01%, 0.001% or 0.0001%. In some specific aspects, the confidence valueis a p value for those modulated RNA transcripts of 10%, 5%, 4%, 3%, 2%,10%, 0.5%, 0.1%, 0.010%, 0.0010% or 0.00010%. In certain specificaspects, an exact test, student t-test or p value for those modulatedRNA transcripts is 10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% and 10%, 5%,4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.01%, 0.001% or 0.0001%, respectively.

[In certain aspects, a further analysis is performed to determine howCompound (I) is changing the amount of an RNA transcript(s). In specificaspects, a further analysis is performed to determine if modulation inthe amount of an RNA transcript(s) in the presence of Compound (I)relative the amount of the RNA transcript(s) in the absence of Compound(I) or a form thereof, or the presence of a negative control is due tochanges in transcription, splicing, and/or stability of the RNAtranscript(s). Techniques known to one skilled in the art may be used todetermine whether Compound (I) changes, e.g., the transcription,splicing and/or stability of an RNA transcript(s).

In certain aspects, the stability of one or more RNA transcripts isdetermined by serial analysis of gene expression (SAGE), differentialdisplay analysis (DD), RNA arbitrary primer (RAP)-PCR, restrictionendonuclease-lytic analysis of differentially expressed sequences(READS), amplified restriction fragment-length polymorphism (ALFP),total gene expression analysis (TOGA), RT-PCR, RT-RPA (recombinasepolymerase amplification), RT-qPCR, RNA-Seq, digital color-coded barcodetechnology, high-density cDNA filter hybridization analysis (HDFCA),suppression subtractive hybridization (SSH), differential screening(DS), cDNA arrays, oligonucleotide chips, or tissue microarrays. Inother aspects, the stability of one or more RNA transcripts isdetermined by Northern blot, RNase protection, or slot blot.

In some aspects, the transcription in a cell(s) or tissue sample isinhibited before (e.g., 5 minutes, 10 minutes, 30 minutes, 1 hour, 2hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36hours, 48 hours, or 72 hours before) or after (e.g., 5 minutes, 10minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12hours, 18 hours, 24 hours, 36 hours, 48 hours, or 72 hours) the cell orthe tissue sample is contacted or cultured with an inhibitor oftranscription, such as α-amanitin, DRB, flavopiridol, triptolide, oractinomycin-D. In other aspects, the transcription in a cell(s) ortissue sample is inhibited with an inhibitor of transcription, such asα-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D, while thecell(s) or tissue sample is contacted or cultured with Compound (I).

In certain aspects, the level of transcription of one or more RNAtranscripts is determined by nuclear run-on assay or an in vitrotranscription initiation and elongation assay. In some aspects, thedetection of transcription is based on measuring radioactivity orfluorescence. In some aspects, a PCR-based amplification step is used.

In specific aspects, the amount of alternatively spliced forms of theRNA transcripts of a particular gene are measured to see if there ismodulation in the amount of one, two or more alternatively spliced formsof the RNA transcripts of the gene. In some aspects, the amount of anisoform(s) encoded by a particular gene is measured to see if there ismodulation in the amount of the isoform(s). In certain aspects, thelevels of spliced forms of RNA are quantified by RT-PCR, RT-qPCR,RNA-Seq, digital color-coded barcode technology, or Northern blot. Inother aspects, sequence-specific techniques may be used to detect thelevels of an individual spliceoform. In certain aspects, splicing ismeasured in vitro using nuclear extracts. In some aspects, detection isbased on measuring radioactivity or fluorescence. Techniques known toone skilled in the art may be used to measure modulation in the amountof alternatively spliced forms of an RNA transcript of a gene andmodulation in the amount of an isoform encoded by a gene.

Examples

To describe in more detail and assist in understanding the presentdescription, the following non-limiting examples are offered to morefully illustrate the scope of the description and are not to beconstrued as specifically limiting the scope thereof. Such variations ofthe present description that may be now known or later developed, whichwould be within the purview of one skilled in the art to ascertain, areconsidered to fall within the scope of the present description and ashereinafter claimed. The examples below illustrate the usefulness of theCNN Model and the 39 CNN Motifs identified herein.

Identification of Genes Affected by Compound (I) Splicing ModulationUsing a Convolutional Neural Network (CNN) Model

A specific deep learning convolutional neural network (CNN) was appliedand optimized to discover nucleotide motifs likely to be responsive tosplicing modulation by a small molecule splicing modulator Compound (I).As described herein, motifs likely to be responsive in 171 additionaldisease-associated genes using OMIM and ClinVar were identified. Asfurther described herein, in vitro validation demonstrated that the CNNModel successfully predicted Compound (I) splice modulation in minigeneassays and in patient-specific cell lines. This approach suggests thatthe integration of genomic datasets, clinical annotation of diseaseassociated variants, and deep learning techniques have significantpotential to predict therapeutic targeting for precision medicine.

The effect on splicing modulation and corresponding splice differencestoward exon inclusion or exclusion was determined by counting the RNASeqreads covering two splice junctions of exon triplets (three consecutiveexons: Exon U, Exon X, Exon D) and the corresponding interveningintrons, then comparing the change in Percent Spliced In (ΔPSI or Δψ) ofthe middle exon (Exon X) after treatment (as shown in FIG. 2A)^(52,53).934 exon triplets were identified showing differential middle exoninclusion or exclusion in response to Compound (I) treatment. Of these,254 were exon inclusion events (Δψ≥0.1 and FDR<0.1) and 680 were exonexclusion events (Δψ≤−0.1 and FDR<0.1) (as shown in FIG. 2B). Compound(I) exhibited selective splicing modulation activity for splicingchanges in 0.58% of all expressed triplets (934 out of 161,097 expressedtriplets). The effect of Compound (I) treatment on genes, as shown inFIG. 2C, demonstrated by reproducible PSI changes (Δψ) determined byRNA-seq, was confirmed. The splicing results were evaluated by RT-PCR inindependent replicate experiments, confirming all the calculated Δψvalues. These results suggest that Compound (I) targets a specificsubset of exons for splicing modulation.

Pre-mRNA splicing is driven by sequence elements throughout exons andintrons. These sequences govern interaction with the spliceosome andsplicing factors and regulate the fate of exon recognition andinclusion^(2,54). These sequence signatures within the exon triplets arethe key determinate of small molecule splicing modulator compoundresponsiveness. To identify such sequences, a convolutional neuralnetwork (CNN) model was trained using the inclusion-response set (254exon triplets), exclusion-response set (680 exon triplets) and theunchanged-response set (382 exon triplets, Δψ≤0.01) identified by RNASeq(see Table 16).

Gene Modulation Using Compound (I)

The effect of Compound (I) on transcriptome-wide splicing as measured byRNA sequence (RNASeq) analysis is provided in Table 16 (where Intron 1is upstream of the affected Exon and Intron 2 is downstream; the Effectshown is Exc, Inc, or Unc representing Exclusion, Inclusion andUnchanged, respectively; C-PSI, T-PSI and ΔPSI are the average PercentSpliced In values for the initial PSI, Treated-PSI and ΔPSI,respectively and the associated p value), in which six differentwildtype (WT) human fibroblast cell lines were treated with Compound (I)and vehicle (DMSO) for seven days.

TABLE 16 Gene Intron1 Exon Intron2 Effect C-PSI T-PSI ΔPSI p valueA1BG-AS1 58859211- 58864687- 58864841- Exc 0.729 0.361 −0.368 5.73E−0458864686 58864840 58865079 AAAS 53708226- 53708535- 53708634- Exc 0.8110.645 −0.166 9.73E−10 53708534 53708633 53708877 AAMDC 77532288-77552065- 77552107- Unc 0.465 0.460 −0.005 8.72E−01 77552064 7755210677553524 ABCA1 107645439- 107646708- 107646850- Exc 0.895 0.724 −0.1724.32E−06 107646707 107646849 107651382 ABCA2 139917505- 139918290-139918293- Unc 0.900 0.902 0.003 9.85E−01 139918289 139918292 139918594ABCA6 67085684- 67087284- 67087404- Exc 0.991 0.852 −0.139 6.61E−0667087283 67087403 67092380 ABCA9 66992156- 67003900- 67004014- Exc 0.9930.553 −0.439 6.55E−22 67003899 67004013 67004202 ABCB6 220079805-220080719- 220080903- Exc 0.979 0.874 −0.104 4.77E−04 220080718220080902 220081085 ABCC3 48752838- 48752992- 48753137- Exc 0.968 0.817−0.150 1.13E−16 48752991 48753136 48753243 ABCC3 48736730- 48738284-48738476- Unc 0.856 0.850 −0.006 9.15E−01 48738283 48738475 48741041ABCD4 74766379- 74766853- 74766972- Unc 0.844 0.849 0.005 9.14E−0174766852 74766971 74769577 ABHD14A- 52018175- 52019223- 52019288- Exc0.950 0.825 −0.125 1.20E−04 ACY1 52019222 52019287 52019376 ABHD16A31668806- 31669851- 31669908- Unc 0.820 0.826 0.006 9.16E−01 3166985031669907 31670926 ABI1 27059275- 27060004- 27060019- Inc 0.559 0.6990.141 8.08E−08 27060003 27060018 27065993 ABI2 204267458- 204276008-204276095- Inc 0.475 0.634 0.158 8.84E−08 204276007 204276094 204281630ABI3BP 100581230- 100581682- 100581754- Exc 0.791 0.629 −0.162 7.19E−09100581681 100581753 100582845 ABI3BP 100581230- 100582846- 100582921-Exc 0.566 0.361 −0.205 3.25E−05 100582845 100582920 100583676 ABI3BP100581230- 100581682- 100581754- Exc 0.404 0.162 −0.241 2.59E−09100581681 100581753 100583676 ABI3BP 100499054- 100506572- 100506647-Unc 0.797 0.792 −0.005 1.77E−01 100506571 100506646 100508297 AC024560.3197348740- 197349058- 197349202- Exc 0.827 0.651 −0.176 5.59E−04197349057 197349201 197350090 AC027612.6 91825060- 91842946- 91843024-Inc 0.380 0.557 0.177 1.59E−05 91842945 91843023 91843393 AC037459.422447255- 22449064- 22449182- Exc 0.864 0.542 −0.322  9.15E−124 2244906322449181 22451245 ACAA1 38170880- 38173087- 38173130- Exc 0.935 0.787−0.148 1.21E−14 38173086 38173129 38173416 ACACA 35564715- 35567381-35567405- Exc 0.816 0.625 −0.191 3.02E−08 35567380 35567404 35578644ACAD10 112147489- 112150302- 112150462- Exc 0.960 0.786 −0.173 7.85E−04112150301 112150461 112153624 ACAD10 112147489- 112148077- 112148170-Unc 0.245 0.239 −0.006 8.44E−01 112148076 112148169 112150301 ACAP31230009- 1230098- 1230197- Unc 0.867 0.859 −0.008 8.80E−01 12300971230196 1230826 ACBD4 43214144- 43214386- 43214507- Exc 0.816 0.628−0.187 3.62E−04 43214385 43214506 43214734 ACBD5 27508787- 27512136-27512169- Inc 0.127 0.253 0.126 5.61E−05 27512135 27512168 27512266 ACCS44102871- 44103615- 44103743- Unc 0.118 0.126 0.008 9.66E−01 4410361444103742 44104718 ACIN1 23551046- 23559191- 23559311- Inc 0.504 0.6110.107 5.87E−05 23559190 23559310 23559730 ACLY 40049428- 40052873-40052903- Inc 0.610 0.792 0.181 1.68E−22 40052872 40052902 40054001ACOT9 23751335- 23754036- 23754134- Unc 0.891 0.887 −0.005 9.58E−0123754035 23754133 23761241 ACOX1 73953648- 73956296- 73956457- Inc 0.6420.791 0.149 1.57E−04 73956295 73956456 73969705 ACSL3 223752607-223765392- 223765499- Inc 0.342 0.507 0.164 1.87E−10 223765391 223765498223773450 ACSL4 108926896- 108939373- 108939426- Exc 0.896 0.729 −0.1675.02E−04 108939372 108939425 108976367 ACTN1 69349310- 69349590-69349773- Exc 0.978 0.863 −0.115 1.11E−92 69349589 69349772 69350884ACTN1 69343958- 69345175- 69345241- Unc 0.102 0.098 −0.003 1.48E−0169345174 69345240 69345705 ACY1 52018175- 52019223- 52019288- Exc 0.9500.825 −0.125 1.20E−04 52019222 52019287 52019376 AD000671.6 36235323-36235527- 36235640- Exc 0.519 0.093 −0.426 1.77E−15 36235526 3623563936236025 ADA 43249789- 43251229- 43251294- Exc 0.943 0.813 −0.1311.85E−05 43251228 43251293 43251469 ADAM15 155032820- 155033239-155033309- Unc 0.797 0.805 0.008 8.01E−01 155033238 155033308 155034720ADAM33 3655341- 3655420- 3655497- Exc 0.970 0.861 −0.108 6.77E−103655419 3655496 3655673 ADAMTSL4 150521976- 150522298- 150522372- Exc0.900 0.716 −0.183 3.37E−07 150522297 150522371 150524680 ADAMTSL4150528843- 150529097- 150529270- Exc 0.956 0.724 −0.231 2.64E−30150529096 150529269 150529414 ADARB1 46603426- 46604389- 46604509- Exc0.761 0.649 −0.113 9.54E−05 46604388 46604508 46604837 ADK 76158338-76285014- 76285185- Exc 0.974 0.833 −0.141 7.08E−16 76285013 7628518476349039 AFMID 76198833- 76200909- 76200982- Inc 0.128 0.647 0.5198.70E−13 76200908 76200981 76202026 AFTPH 64800203- 64806620- 64806681-Unc 0.889 0.889 −0.001 9.61E−01 64806619 64806680 64812555 AFTPH64800203- 64806620- 64808408- Unc 0.838 0.832 −0.006 9.12E−01 6480661964808407 64812555 AHI1 135813430- 135816952- 135817037- Inc 0.370 0.5840.214 7.37E−04 135816951 135817036 135818325 AK4 65613349- 65613961-65614236- Unc 0.694 0.703 0.010 8.91E−01 65613960 65614235 65656392AKAP11 42869879- 42871184- 42871319- Exc 0.944 0.786 −0.158 2.49E−0742871183 42871318 42872668 AKAP13 86199019- 86201768- 86201822- Inc0.740 0.874 0.134 3.44E−04 86201767 86201821 86207793 AKIP1 8933219-8934000- 8934081- Exc 0.528 0.339 −0.189 1.79E−06 8933999 89340808936372 AKIP1 8936478- 8938834- 8938915- Exc 0.983 0.769 −0.214 1.28E−348938833 8938914 8940883 AKR1A1 46033850- 46034157- 46034357- Exc 0.9410.687 −0.254 3.92E−47 46034156 46034356 46034598 AL163636.6 21152918-21161706- 21161810- Inc 0.172 0.283 0.112 1.19E−06 21161705 2116180921167513 ALDH3B1 67782930- 67785997- 67786107- Exc 0.932 0.792 −0.1401.96E−08 67785996 67786106 67786241 ALDH4A1 19212123- 19212958-19213006- Exc 0.958 0.792 −0.166 4.30E−04 19212957 19213005 19215855ALKBH1 78146314- 78161081- 78161244- Exc 0.967 0.828 −0.139 3.85E−0478161080 78161243 78170711 ALKBH3 43911379- 43923066- 43923276- Exc0.950 0.802 −0.148 2.58E−06 43923065 43923275 43940587 ALKBH3 43911379-43913591- 43913680- Exc 0.858 0.549 −0.309 8.23E−17 43913590 4391367943923065 AMBRA1 46529921- 46534277- 46534364- Unc 0.637 0.640 0.0036.56E−01 46534276 46534363 46563494 AMDHD2 2571125- 2577562- 2577617-Unc 0.810 0.813 0.003 9.67E−01 2577561 2577616 2577773 AMIGO2 47472849-47472925- 47473032- Unc 0.540 0.534 −0.006 8.12E−01 47472924 4747303147473244 AMMECR1L 128631847- 128641777- 128641887- Exc 0.970 0.829−0.142 1.23E−05 128641776 128641886 128643383 AMOTL1 94501727- 94528177-94528327- Unc 0.757 0.757 −0.001 9.49E−01 94528176 94528326 94532555AMPD2 110162901- 110167925- 110168056- Exc 0.844 0.690 −0.154 3.82E−04110167924 110168055 110168283 AMZ2P1 62969046- 62969360- 62969636- Unc0.832 0.836 0.004 8.86E−01 62969359 62969635 62970672 ANAPC11 79849710-79851428- 79851491- Unc 0.705 0.708 0.003 9.31E−01 79851427 7985149079852342 ANK2 114290962- 114293689- 114293782- Exc 0.671 0.422 −0.2494.15E−06 114293688 114293781 114294245 ANKRD10 111545611- 111552877-111553009- Exc 0.380 0.100 −0.280 4.11E−21 111552876 111553008 111558379ANKRD10 1115456Il- 111552877- 111553042- Exc 0.390 0.088 −0.302 4.37E−24li 1552876 111553041 111558379 ANKRD11 89357592- 89358089- 89358186- Inc0.347 0.523 0.176 3.41E−09 89358088 89358185 89371613 ANKRD17 74000980-74005248- 74006001- Unc 0.859 0.862 0.003 9.24E−01 74005247 7400600074007457 ANKRD36 97875447- 97875537- 97875610- Exc 0.301 0.066 −0.2351.47E−04 97875536 97875609 97877282 ANO6 45610175- 45695797- 45695877-Exc 0.882 0.765 −0.117 1.59E−10 45695796 45695876 45725077 ANO645610175- 45664245- 45664308- Unc 0.124 0.133 0.009 6.17E−01 4566424445664307 45695796 ANXA2 60678286- 60689457- 60689538- Inc 0.054 0.1540.100 0.00E+00 60689456 60689537 60690141 AOX1 201474138- 201476107-201476217- Unc 0.904 0.896 −0.008 4.94E−01 201476106 201476216 201477331AP1G1 71799488- 71801780- 71801789- Inc 0.251 0.489 0.238 4.95E−1671801779 71801788 71803525 AP2M1 183898040- 183898433- 183898530- Exc0.423 0.261 −0.162 1.38E−70 183898432 183898529 183898636 AP2M1183898040- 183898433- 183898439- Exc 0.605 0.423 −0.182  3.32E−109183898432 183898438 183898636 APBB2 41035322- 41067593- 41067691- Exc0.698 0.538 −0.161 9.66E−05 41067592 41067690 41102655 APOL1 36651046-36653129- 36653183- Exc 0.862 0.753 −0.109 1.35E−06 36653128 3665318236653364 APP 27354791- 27369675- 27369732- Exc 0.739 0.590 −0.149 8.80E−131 27369674 27369731 27372329 ARHGAP12 32120729- 32128565-32128640- Inc 0.554 0.896 0.342 4.84E−20 32128564 32128639 32132388ARHGAP12 32141526- 32142994- 32143135- Inc 0.788 0.929 0.140 1.26E−1032142993 32143134 32150322 ARHGAP23 36654069- 36654656- 36654753- Exc0.821 0.687 −0.134 6.60E−20 36654655 36654752 36656838 ARHGEF10 1824901-1828214- 1828331- Inc 0.536 0.725 0.190 4.24E−10 1828213 1828330 1830800ARHGEF10 1772280- 1791519- 1791603- Unc 0.859 0.860 0.002 9.61E−011791518 1791602 1806125 ARHGEF10L 17958962- 17961043- 17961058- Exc0.874 0.744 −0.130 1.03E−03 17961042 17961057 17961329 ARHGEF12120300227- 120300421- 120300541- Exc 0.810 0.709 −0.102 2.31E−06120300420 120300540 120302479 ARHGEF25 58008801- 58009020- 58009098- Exc0.959 0.856 −0.103 8.02E−06 58009019 58009097 58009294 ARID4B 235359431-235377084- 235377342- Exc 0.662 0.512 −0.150 2.83E−04 235377083235377341 235383107 ARID5A 97213255- 97215058- 97215197- Unc 0.520 0.5230.004 7.80E−01 97215057 97215196 97215489 ARIH2 48960245- 48962151-48962405- Exc 0.530 0.371 −0.159 1.77E−04 48962150 48962404 48964894ARIH2 48960245- 48962151- 48962273- Exc 0.646 0.470 −0.175 3.49E−0648962150 48962272 48964894 ARIH2 48960245- 48982569- 48982615- Unc 0.8970.906 0.009 9.17E−01 48982568 48982614 48999044 ARIH2 48965247-48982569- 48982615- Unc 0.289 0.292 0.002 9.70E−01 48982568 4898261448999044 ARMC10 102727212- 102732924- 102733101- Unc 0.780 0.781 0.0029.84E−01 102732923 102733100 102737723 ARSJ 114824832- 114827821-114827902- Unc 0.103 0.103 0.000 9.59E−01 114827820 114827901 114899592ARSK 94903754- 94916596- 94916647- Inc 0.039 0.219 0.180 1.16E−0694916595 94916646 94918619 ASAP2 9528676- 9531191- 9531326- Inc 0.7000.900 0.200 4.73E−06 9531190 9531325 9533610 ASCC2 30221247- 30221611-30221770- Exc 0.863 0.730 −0.133 4.24E−05 30221610 30221769 30228233ASCC2 30228332- 30230478- 30230540- Unc 0.605 0.615 0.009 9.35E−0130230477 30230539 30234166 ASL 65551650- 65551731- 65551809- Exc 0.8500.744 −0.106 3.00E−04 65551730 65551808 65552320 ASPH 62555993-62556504- 62556561- Exc 0.839 0.726 −0.113 8.37E−70 62556503 6255656062557158 ASPH 62557192- 62559309- 62559438- Inc 0.786 0.955 0.169 1.59E−243 62559308 62559437 62563608 ASUN 27067062- 27067341- 27067512-Exc 0.834 0.705 −0.128 1.87E−04 27067340 27067511 27068934 ASXL131017235- 31017704- 31017857- Exc 0.851 0.696 −0.155 9.56E−04 3101770331017856 31019123 ATG10 81474407- 81548381- 81548479- Inc 0.811 0.9700.159 1.16E−03 81548380 81548478 81571963 ATG12 115173462- 115176194-115176310- Unc 0.624 0.633 0.009 8.94E−01 115176193 115176309 115176514ATG13 46639926- 46651595- 46651651- Unc 0.845 0.854 0.010 7.41E−0146651594 46651650 46665828 ATG13 46639441- 46639875- 46639926- Unc 0.2240.228 0.003 9.18E−01 46639874 46639925 46651594 ATG16L1 234181699-234182367- 234182424- Exc 0.763 0.487 −0.277 9.35E−10 234182366234182423 234183321 ATG4B 242590751- 242592722- 242592785- Unc 0.1090.110 0.001 9.93E−01 242592721 242592784 242592926 ATG7 11340330-11340836- 11340891- Exc 0.993 0.892 −0.101 4.09E−07 11340835 1134089011348416 ATG9A 220079805- 220080719- 220080903- Exc 0.979 0.874 −0.1044.77E−04 220080718 220080902 220081085 ATP2C1 130613182- 130613575-130613620- Inc 0.666 0.818 0.152 3.71E−07 130613574 130613619 130649259ATP2C1 130613182- 130613552- 130613620- Inc 0.677 0.824 0.146 4.82E−07130613551 130613619 130649259 ATP2C1 130613182- 130613434- 130613620-Inc 0.684 0.826 0.142 7.77E−07 130613433 130613619 130649259 ATP5C17844818- 7848937- 7848974- Unc 0.215 0.207 −0.007 7.79E−01 78489367848973 7849621 ATP5SL 41939579- 41942297- 41942378- Inc 0.850 0.9640.114 2.08E−09 41942296 41942377 41944122 ATP6C 2571125- 2577562-2577617- Unc 0.810 0.813 0.003 9.67E−01 2577561 2577616 2577773 ATPAF147118301- 47119489- 47119540- Exc 0.964 0.745 −0.219 3.04E−29 4711948847119539 47123798 ATXN1 16658133- 16753464- 16753579- Exc 0.820 0.688−0.132 3.78E−04 16753463 16753578 16761528 ATXN3 92559663- 92560090-92560176- Exc 0.950 0.785 −0.165 1.73E−07 92560089 92560175 92562436ATXN3 92559663- 92560090- 92560195- Exc 0.908 0.636 −0.271 5.26E−0792560089 92560194 92562436 AUP1 74755617- 74755878- 74756063- Exc 0.9280.813 −0.114 4.48E−17 74755877 74756062 74756258 AUTS2 70236631-70239014- 70239086- Exc 0.901 0.758 −0.143 1.11E−03 70239013 7023908570240342 AVL9 32615685- 32619831- 32619885- Exc 0.972 0.592 −0.3794.43E−19 32619830 32619884 32620413 B3GALNT1 160804577- 160818927-160819022- Inc 0.700 0.864 0.164 6.43E−04 160818926 160819021 160821214B3GALNT1 160804577- 160807732- 160807851- Unc 0.150 0.156 0.007 8.87E−01160807731 160807850 160818926 BAG6 31607004- 31607277- 31607424- Exc0.597 0.458 −0.139 2.29E−11 31607276 31607423 31607975 BANP 88017866-88037901- 88038018- Inc 0.825 0.985 0.160 5.85E−04 88037900 8803801788039695 BAX 49458220- 49458805- 49458857- Exc 0.937 0.832 −0.1051.22E−06 49458804 49458856 49459454 BAZ1A 35255208- 35255332- 35255428-Exc 0.877 0.692 −0.185 9.82E−04 35255331 35255427 35261980 BAZ2A57011317- 57024560- 57024650- Unc 0.551 0.549 −0.002 9.42E−01 5702455957024649 57029965 BBS4 73004649- 73007632- 73007744- Exc 0.982 0.750−0.232 1.36E−11 73007631 73007743 73009118 BBS5 170349520- 170350251-170350347- Exc 1.000 0.824 −0.176 7.16E−07 170350250 170350346 170355995BBX 107497367- 107508634- 107508724- Inc 0.640 0.757 0.117 5.10E−05107508633 107508723 107510086 BCAR1 75269885- 75271081- 75271243- Exc0.908 0.761 −0.147 5.95E−05 75271080 75271242 75276367 BCAR1 75269885-75270780- 75270897- Exc 0.982 0.797 −0.185 3.94E−21 75270779 7527089675271080 BCAR1 75269885- 75270726- 75270897- Exc 0.959 0.642 −0.3172.84E−18 75270725 75270896 75271080 BCL2L2 23777409- 23778025- 23778142-Unc 0.905 0.898 −0.007 9.53E−01 23778024 23778141 23780181 BCOR39930413- 39930890- 39930944- Exc 0.661 0.452 −0.209 8.56E−04 3993088939930943 39931601 BEND6 56857354- 56879260- 56879324- Unc 0.101 0.1000.000 9.69E−01 56879259 56879323 56879930 BIN1 127808489- 127808730-127808820- Exc 0.878 0.726 −0.152 1.40E−04 127808729 127808819 127815048BIN1 127808489- 127808730- 127808820- Exc 0.884 0.712 −0.172 6.43E−05127808729 127808819 127816586 BIRC6 32658873- 32660564- 32660654- Exc0.787 0.552 −0.235 3.99E−06 32660563 32660653 32661120 BIRC6 32800434-32815873- 32816046- Unc 0.108 0.108 0.000 8.86E−01 32815872 3281604532818981 BLOC1S6 45879724- 45884333- 45884475- Exc 0.724 0.597 −0.1275.48E−04 45884332 45884474 45897625 BLOC1S6 45879724- 45884333-45884475- Exc 0.779 0.516 −0.263 3.98E−23 45884332 45884474 45895297BLOC1S6 45879724- 45895298- 45895386- Unc 0.834 0.841 0.007 7.47E−0145895297 45895385 45897625 BMP2K 79800046- 79808328- 79808439- Exc 0.5540.274 −0.281 2.14E−11 79808327 79808438 79831763 BOK 242501892-242509540- 242509704- Exc 0.874 0.748 −0.126 4.30E−04 242509539242509703 242511711 BPTF 65955992- 65959449- 65959623- Exc 0.585 0.199−0.386 5.43E−23 65959448 65959622 65960327 BPTF 65871861- 65882244-65882433- Inc 0.665 0.832 0.167 2.66E−04 65882243 65882432 65887959 BRD8137492957- 137495244- 137495289- Exc 0.610 0.401 −0.208 1.57E−11137495243 137495288 137495757 BRD8 137503768- 137504159- 137504378- Unc0.735 0.739 0.004 9.45E−01 137504158 137504377 137504910 BRD8 137501798-137502207- 137502417- Unc 0.729 0.722 −0.007 8.43E−01 137502206137502416 137503622 BROX 222886285- 222889026- 222889143- Inc 0.8630.968 0.105 5.17E−07 222889025 222889142 222892266 BTBD19 45274579-45275885- 45276099- Exc 0.992 0.721 −0.270 1.50E−07 45275884 4527609845276225 BTBD19 45274579- 45275885- 45275922- Exc 0.988 0.668 −0.3203.77E−06 45275884 45275921 45276225 BTBD3 11871603- 11898426- 11898660-Unc 0.230 0.232 0.001 9.69E−01 11898425 11898659 11898981 BTF3L452522052- 52525507- 52525574- Unc 0.893 0.902 0.008 5.65E−01 5252550652525573 52530496 C10orf118 115923089- 115932900- 115933025- Unc 0.2380.228 −0.010 9.66E−01 115932899 115933024 115933773 C11orf30 76169403-76170980- 76171130- Inc 0.629 0.903 0.274 3.48E−04 76170979 7617112976174864 C11orf30 76169403- 76170977- 76171130- Inc 0.729 0.936 0.2077.07E−05 76170976 76171129 76174864 C11orf30 76248995- 76250643-76250685- Unc 0.754 0.753 −0.001 8.84E−01 76250642 76250684 76253259C11orf57 111945083- 111945611- 111945641- Unc 0.395 0.390 −0.0059.74E−01 111945610 111945640 111946290 C11orf70 101929687- 101937216-101937383- Exc 0.973 0.843 −0.130 1.77E−04 101937215 101937382 101946603C12orf29 88429516- 88433925- 88434043- Inc 0.745 0.897 0.152 1.32E−0588433924 88434042 88436601 C14orf159 91580628- 91611565- 91611658- Unc0.121 0.124 0.003 9.48E−01 91611564 91611657 91623982 C16orf13 684798-685518- 685775- Exc 0.760 0.447 −0.313 4.99E−04 685517 685774 686093C1orf85 156264357- 156264550- 156264808- Exc 0.844 0.698 −0.147 4.56E−15156264549 156264807 156265316 C1RL 7254684- 7260847- 7261076- Exc 0.8650.689 −0.176 6.02E−11 7260846 7261075 7261705 C2CD5 22610096- 22612426-22612477- Inc 0.523 0.770 0.247 3.77E−06 22612425 22612476 22622642C2CD5 22610096- 22611418- 22611490- Inc 0.854 1.000 0.146 1.04E−0622611417 22611489 22612425 C2CD5 22610096- 22611418- 22611520- Inc 0.8811.000 0.119 3.44E−07 22611417 22611519 22612425 C2orf76 120075080-120078730- 120078781- Unc 0.865 0.858 −0.008 9.03E−01 120078729120078780 120097402 C3orf18 50599179- 50602897- 50603293- Inc 0.4270.627 0.200 5.28E−04 50602896 50603292 50604893 C5orf42 37162669-37164375- 37164430- Exc 0.973 0.869 −0.103 7.10E−04 37164374 3716442937165640 C5orf45 179275067- 179280197- 179280277- Inc 0.132 0.390 0.2583.00E−06 179280196 179280276 179280377 C8orf59 86129732- 86131552-86131593- Inc 0.127 0.317 0.191 1.66E−25 86131551 86131592 86132534C8orf59 86129732- 86131465- 86131593- Inc 0.105 0.225 0.119 9.55E−1486131464 86131592 86132534 C9orf156 100672899- 100675155- 100675258- Inc0.130 0.274 0.145 1.03E−03 100675154 100675257 100675682 C9orf156100675841- 100678446- 100678621- Unc 0.758 0.762 0.004 8.93E−01100678445 100678620 100684699 C9orf85 74562029- 74586421- 74586535- Exc0.609 0.362 −0.247 1.04E−04 74586420 74586534 74597572 CA5BP1 15706982-15711086- 15711182- Inc 0.727 0.908 0.181 1.00E−03 15711085 1571118115720904 CACNA1C 2721180- 2742795- 2742879- Unc 0.201 0.192 −0.0099.98E−01 2742794 2742878 2743462 CALU 128388859- 128394316- 128394510-Inc 0.625 0.807 0.182  2.09E−164 128394315 128394509 128394582 CAMK2D114375672- 114376882- 114376978- Exc 0.251 0.079 −0.173 8.44E−18114376881 114376977 114378490 CAMK2G 75583843- 75585037- 75585106- Unc0.881 0.890 0.009 9.67E−01 75585036 75585105 75597225 CAMSAP1 138742308-138754313- 138754455- Unc 0.817 0.816 −0.001 9.89E−01 138754312138754454 138758301 CAMTA1 6845636- 6880241- 6880311- Inc 0.732 0.8950.163 4.82E−15 6880240 6880310 6885151 CAPN10 241535939- 241536098-241536360- Unc 0.895 0.887 −0.008 9.33E−01 241536097 241536359 241537304CAPN7 15283761- 15287033- 15287179- Exc 0.963 0.863 −0.101 2.98E−0815287032 15287178 15288238 CAPN7 15288965- 15292482- 15292531- Exc 0.9690.852 −0.117 1.75E−06 15292481 15292530 15292622 CAPRIN2 30869611-30872013- 30873850- Exc 0.835 0.625 −0.210 9.09E−11 30872012 3087384930876192 CAPRIN2 30869611- 30872013- 30872160- Exc 0.768 0.538 −0.2302.34E−08 30872012 30872159 30876192 CAPRIN2 30869611- 30873745-30873850- Exc 0.722 0.471 −0.251 4.48E−09 30873744 30873849 30876192CAPRIN2 30884445- 30886563- 30886646- Exc 0.473 0.150 −0.323 6.22E−1630886562 30886645 30887901 CARD8 48737801- 48741640- 48741790- Exc 0.6670.426 −0.242 6.35E−05 48741639 48741789 48744218 CARD8 48737801-48741640- 48741784- Exc 0.477 0.185 −0.293 7.65E−05 48741639 4874178348744218 CARF 203782767- 203806583- 203806704- Unc 0.801 0.806 0.0059.25E−01 203806582 203806703 203817281 CARKD 111276627- 111277537-111277626- Exc 0.962 0.771 −0.191 4.83E−12 111277536 111277625 111279785CASP3 185559623- 185569619- 185569786- Inc 0.330 0.471 0.141 7.63E−05185569618 185569785 185570548 CAST 96058403- 96062458- 96062564- Exc0.278 0.161 −0.117 4.69E−21 96062457 96062563 96063192 CAST 96058403-96062498- 96062564- Exc 0.425 0.268 −0.156 1.16E−32 96062497 9606256396063192 CCBL2 89435151- 89453935- 89454035- Inc 0.399 0.517 0.1193.36E−04 89453934 89454034 89458267 CCDC126 23637671- 23643705-23643899- Unc 0.337 0.340 0.003 9.87E−01 23643704 23643898 23650789CCDC136 128445956- 128446291- 128446450- Unc 0.872 0.871 −0.001 9.71E−01128446290 128446449 128446741 CCDC25 27605797- 27606012- 27606116- Exc0.871 0.699 −0.171 2.16E−10 27606011 27606115 27610028 CCDC25 27610105-27614236- 27614288- Unc 0.813 0.813 0.000 9.07E−01 27614235 2761428727619935 CCDC90B 82985784- 82989769- 82989873- Exc 0.857 0.745 −0.1131.89E−11 82989768 82989872 82991183 CCNDBP1 43477806- 43478018-43478078- Exc 0.923 0.767 −0.156 9.47E−08 43478017 43478077 43481396CCNL1 156868171- 156869518- 156869720- Exc 0.326 0.204 −0.123 2.22E−04156869517 156869719 156869965 CCNL2 1326246- 1326677- 1326956- Unc 0.8900.889 −0.001 9.31E−01 1326676 1326955 1328058 CCNT1 49089613- 49089782-49089946- Unc 0.876 0.872 −0.005 9.13E−01 49089781 49089945 49091920CCNYL1 208591601- 208598671- 208598772- Unc 0.795 0.792 −0.002 4.41E−01208598670 208598771 208602134 CD27-AS1 6557904- 6560036- 6560147- Unc0.432 0.429 −0.003 9.65E−01 6560035 6560146 6560634 CD27-AS1 6557904-6559507- 6560147- Unc 0.533 0.525 −0.008 8.65E−01 6559506 65601466560634 CD44 35211520- 35232793- 35232997- Inc 0.595 0.873 0.2775.56E−09 35232792 35232996 35236398 CD46 207940541- 207941124-207941169- Exc 0.653 0.522 −0.131 9.35E−20 207941123 207941168 207943665CD46 207959028- 207963598- 207963691- Inc 0.527 0.748 0.221 6.66E−57207963597 207963690 207966863 CD55 207512763- 207513736- 207513854- Exc0.278 0.162 −0.116 4.30E−09 207513735 207513853 207532890 CD99P12541495- 2544638- 2544684- Exc 0.966 0.694 −0.272 3.51E−05 25446372544683 2556014 CD99P1 2537539- 2540731- 2540776- Exc 0.599 0.141 −0.4583.02E−12 2540730 2540775 2541425 CDC14B 99272072- 99277931- 99278075-Exc 0.458 0.228 −0.230 1.57E−09 99277930 99278074 99284787 CDC14B99266072- 99271955- 99272072- Inc 0.547 0.795 0.248 1.82E−08 9927195499272071 99277930 CDC16 115000608- 115002120- 115002175- Exc 0.870 0.559−0.311 2.24E−37 115002119 115002174 115002273 CDC42BPA 227300124-227300372- 227300615- Unc 0.779 0.775 −0.004 9.88E−01 227300371227300614 227307504 CDCA7L 21948126- 21951235- 21951370- Unc 0.738 0.7470.009 8.31E−01 21951234 21951369 21956371 CDK16 47078064- 47081672-47081742- Inc 0.286 0.566 0.280 8.90E−04 47081671 47081741 47082950CDK16 47078505- 47081660- 47081742- Inc 0.094 0.246 0.152 2.82E−0647081659 47081741 47082950 CDK16 47078505- 47081660- 47081780- Inc 0.0560.169 0.113 3.41E−05 47081659 47081779 47082950 CDK5RAP2 123220901-123222850- 123223026- Unc 0.858 0.858 0.000 9.52E−01 123222849 123223025123230137 CEP164 117252585- 117253512- 117253659- Unc 0.235 0.229 −0.0069.69E−01 117253511 117253658 117257918 CEP290 88447524- 88448117-88448191- Inc 0.761 0.941 0.180 1.02E−07 88448116 88448190 88449352 CHD37810807- 7810919- 7811021- Exc 0.533 0.342 −0.191 6.58E−16 78109187811020 7811211 CHEK2 29095926- 29099493- 29099555- Exc 0.613 0.260−0.353 6.09E−08 29099492 29099554 29105993 CHKB 51018232- 51018486-51018512- Exc 0.958 0.848 −0.110 5.70E−05 51018485 51018511 51018618CIRBP 1272051- 1273600- 1273715- Unc 0.128 0.129 0.001 9.31E−01 12735991273714 1274305 CIRBP 1272051- 1273493- 1273715- Unc 0.152 0.144 −0.0078.95E−01 1273492 1273714 1274305 CKLF 66586697- 66592093- 66592252- Exc0.541 0.438 −0.103 5.18E−04 66592092 66592251 66597024 CLASP1 122165292-122166600- 122166624- Inc 0.165 0.429 0.264 5.96E−14 122166599 122166623122168441 CLASP2 33592888- 33600617- 33600668- Unc 0.637 0.628 −0.0099.35E−01 33600616 33600667 33600798 CLCN6 11888277- 11888515- 11888682-Exc 0.604 0.333 −0.271 5.43E−06 11888514 11888681 11889252 CLK1201724470- 201724848- 201724939- Inc 0.451 0.655 0.204 2.02E−11201724847 201724938 201725960 CMC1 28283304- 28304782- 28304872- Inc0.748 0.878 0.130 1.98E−04 28304781 28304871 28357823 CNOT10 32804356-32805947- 32805983- Exc 1.000 0.899 −0.101 2.05E−05 32805946 3280598232806173 COL12A1 75875496- 75884754- 75885027- Inc 0.758 0.876 0.1180.00E+00 75884753 75885026 75887378 COL16A1 32145287- 32145405-32145453- Exc 0.543 0.400 −0.143 1.15E−23 32145404 32145452 32145642COL16A1 32134457- 32136157- 32136248- Exc 0.349 0.163 −0.186 5.75E−2732136156 32136247 32137215 COL16A1 32134457- 32136203- 32136248- Exc0.508 0.277 −0.231 2.46E−41 32136202 32136247 32137215 COL6A3 238296828-238303230- 238303848- Exc 0.394 0.175 −0.219 9.35E−95 238303229238303847 238305369 COL6A3 238290143- 238296225- 238296828- Inc 0.3100.501 0.191  2.58E−146 238296224 238296827 238305369 COPB2 139102278-139103846- 139104043- Inc 0.457 0.696 0.239 4.28E−04 139103845 139104042139108310 COPS7A 6833985- 6837092- 6837168- Exc 0.870 0.743 −0.1271.13E−17 6837091 6837167 6837388 COPS8 237994686- 237995375- 237995440-Inc 0.080 0.311 0.230 1.16E−37 237995374 237995439 237995769 COQ674425928- 74426118- 74426226- Exc 0.943 0.796 −0.147 1.71E−06 7442611774426225 74427875 COX20 244999059- 245005246- 245005361- Exc 0.649 0.446−0.203 1.39E−13 245005245 245005360 245005496 CPEB2 15034836- 15042088-15042112- Exc 0.257 0.132 −0.125 8.15E−04 15042087 15042111 15054037CPNE1 34220846- 34246852- 34246937- Unc 0.361 0.358 −0.003 9.59E−0134246851 34246936 34252681 CPSF7 61188046- 61188664- 61188730- Inc 0.0650.211 0.146 3.45E−14 61188663 61188729 61188861 CPT1C 50194598-50195078- 50195211- Exc 0.503 0.145 −0.358 3.72E−05 50195077 5019521050195495 CPT1C 50194598- 50195078- 50195147- Exc 0.651 0.285 −0.3665.73E−06 50195077 50195146 50195495 CRAT 131870357- 131871458-131871557- Exc 0.574 0.424 −0.150 5.12E−05 131871457 131871556 131872761CREBBP 3824695- 3827614- 3827659- Inc 0.836 0.969 0.133 2.33E−10 38276133827658 3828011 CRLS1 5990559- 5996007- 5996137- Exc 0.992 0.889 −0.1031.14E−06 5996006 5996136 6012657 CRNDE 54953122- 54954210- 54954251- Exc0.973 0.867 −0.106 2.55E−09 54954209 54954250 54957496 CRYZ 75190519-75196066- 75196105- Exc 0.196 0.091 −0.105 1.56E−04 75196065 7519610475198639 CRYZ 75172679- 75172787- 75172889- Exc 0.838 0.322 −0.5161.73E−58 75172786 75172888 75175781 CSAD 53554629- 53554911- 53554976-Exc 0.398 0.224 −0.174 6.03E−04 53554910 53554975 53555056 CSDE1115279477- 115280092- 115280185- Unc 0.104 0.096 −0.008 2.11E−01115280091 115280184 115280583 CSNK1A1 148892773- 148897357- 148897441-Unc 0.113 0.116 0.003 7.55E−01 148897356 148897440 148899852 CTDSPL37988703- 37998602- 37998635- Exc 0.596 0.336 −0.261 1.76E−10 3799860137998634 38006061 CTIF 46065684- 46066129- 46066203- Unc 0.235 0.2410.006 9.23E−01 46066128 46066202 46145908 CTSB 11710989- 11721885-11721973- Unc 0.220 0.219 −0.001 9.29E−01 11721884 11721972 11725509CUTC 101507148- 101510126- 101510154- Exc 0.509 0.240 −0.269 5.92E−10101510125 101510153 101514285 CWC25 36966019- 36966529- 36966654- Exc0.181 0.024 −0.157 6.59E−08 36966528 36966653 36966720 CYB561D250388992- 50389440- 50389478- Exc 0.959 0.823 −0.136 2.79E−05 5038943950389477 50390671 CYLD 50776753- 50778641- 50778778- Inc 0.441 0.8560.415 6.01E−15 50778640 50778777 50783486 CYP20A1 204131405- 204143296-204143412- Exc 0.974 0.830 −0.145 1.01E−04 204143295 204143411 204144781CYP20A1 204103858- 204110569- 204110619- Exc 0.700 0.410 −0.290 2.73E−05204110568 204110618 204116689 DAB2 39394524- 39417291- 39417387- Inc0.138 0.334 0.196 1.02E−04 39417290 39417386 39418282 DBT 100671858-100672001- 100672193- Exc 0.982 0.880 −0.103 2.36E−04 100672000100672192 100676249 DCAF10 37819399- 37842086- 37842284- Exc 0.661 0.533−0.128 5.29E−04 37842085 37842283 37854776 DCAF11 24586603- 24586877-24586942- Exc 0.982 0.828 −0.154 1.63E−15 24586876 24586941 24587263DCAF17 172325541- 172330376- 172330486- Exc 0.962 0.826 −0.135 1.29E−03172330375 172330485 172333369 DCAF8 160213825- 160231075- 160231149- Inc0.762 0.864 0.102 2.04E−04 160231074 160231148 160231906 DCAF8160210161- 160213750- 160213825- Unc 0.907 0.899 −0.009 5.77E−01160213749 160213824 160231074 DCP1A 53326858- 53338207- 53338321- Inc0.890 0.990 0.100 3.80E−04 53338206 53338320 53346270 DCTD 183836729-183837572- 183837693- Unc 0.232 0.235 0.003 9.85E−01 183837571 183837692183838463 DCTD 183836729- 183837572- 183837693- Unc 0.126 0.122 −0.0049.67E−01 183837571 183837692 183838440 DCUN1D5 102937297- 102953477-102953569- Inc 0.856 0.993 0.137 8.56E−23 102953476 102953568 102953984DDB2 47256224- 47256308- 47256486- Exc 0.923 0.772 −0.151 9.72E−0947256307 47256485 47256820 DGKA 56331837- 56332295- 56332345- Exc 0.9990.873 −0.126 8.04E−15 56332294 56332344 56332698 DGUOK 74154180-74166037- 74166150- Unc 0.285 0.287 0.002 9.97E−01 74166036 7416614974173845 DHRSX 2209645- 2310395- 2310516- Exc 0.127 0.024 −0.1032.86E−11 2310394 2310515 2326785 DIMT1 61686810- 61687998- 61688062- Exc0.991 0.851 −0.140 4.42E−19 61687997 61688061 61688752 DIS3 73355142-73355427- 73355495- Exc 0.338 0.170 −0.168 3.13E−04 73355426 7335549473355742 DIS3 73352519- 73354984- 73355142- Inc 0.537 0.720 0.1838.07E−05 73354983 73355141 73355426 DLG1 196876668- 196888511-196888610- Exc 0.613 0.500 −0.113 3.68E−05 196888510 196888609 196921295DLGAP1-AS1 3594483- 3596577- 3596674- Unc 0.832 0.834 0.002 8.24E−013596576 3596673 3597173 DMD 31191722- 31196049- 31196088- Exc 0.4950.086 −0.409 9.35E−12 31196048 31196087 31196785 DMKN 35990932-35991280- 35991322- Unc 0.224 0.230 0.006 7.69E−01 35991279 3599132135991434 DMTF1 86781872- 86783706- 86783845- Exc 0.219 0.076 −0.1443.88E−04 86783705 86783844 86792810 DMTF1 86781872- 86792555- 86792649-Exc 0.254 0.098 −0.157 5.81E−05 86792554 86792648 86792810 DMTF186823419- 86824000- 86824145- Exc 0.944 0.779 −0.165 1.51E−14 8682399986824144 86824346 DMWD 46287549- 46287899- 46287974- Unc 0.648 0.642−0.006 9.50E−01 46287898 46287973 46288851 DNAAF2 50092767- 50094730-50094874- Unc 0.680 0.673 −0.007 9.48E−01 50094729 50094873 50100004DNAJC14 56222499- 56223273- 56223421- Unc 0.764 0.767 0.003 9.33E−0156223272 56223420 56224479 DNAJC19 180703785- 180704786- 180704811- Inc0.676 0.811 0.135 1.53E−05 180704785 180704810 180705810 DNAJC19180703785- 180704731- 180704811- Inc 0.808 0.910 0.102 1.73E−08180704730 180704810 180705810 DNAJC2 102967132- 102967779- 102967826-Exc 0.152 0.051 −0.102 1.95E−05 102967778 102967825 102968102 DNAJC2431392407- 31436358- 31436497- Unc 0.904 0.896 −0.008 9.12E−01 3143635731436496 31447833 DNM1L 32890096- 32891198- 32891231- Exc 0.271 0.050−0.221 4.56E−18 32891197 32891230 32892997 DNM1L 32890877- 32891198-32891231- Exc 0.547 0.180 −0.366 2.76E−09 32891197 32891230 32892997DNM1L 32890096- 32890799- 32890877- Inc 0.545 0.788 0.243 2.25E−0432890798 32890876 32891197 DNMT1 10288044- 10290863- 10290911- Exc 0.2790.138 −0.141 3.31E−04 10290862 10290910 10291025 DOCK5 25240295-25246325- 25246458- Inc 0.085 0.336 0.251 2.26E−12 25246324 2524645725246606 DOCK7 62943497- 62953069- 62953084- Exc 0.912 0.691 −0.2211.17E−04 62953068 62953083 62954604 DPH3 16302337- 16305662- 16305737-Inc 0.511 0.757 0.247 1.39E−21 16305661 16305736 16306275 DPH7140470855- 140471922- 140472056- Unc 0.854 0.850 −0.004 9.52E−01140471921 140472055 140473076 DPH7 140470620- 140471922- 140472056- Unc0.724 0.718 −0.006 8.33E−01 140471921 140472055 140473076 DPM1 49552800-49557402- 49557493- Unc 0.894 0.893 −0.001 9.37E−01 49557401 4955749249558567 DPY19L4 95732243- 95738559- 95738670- Exc 0.975 0.874 −0.1014.43E−04 95738558 95738669 95750596 DRAM2 111663316- 111667364-111667504- Exc 0.924 0.755 −0.169 2. ISE−17  111667363 111667503111668848 DRAM2 111680209- 1116822lO- 111682334- Inc 0.466 0.668 0.2025.23E−07 111682209 ll 1682333 111682659 DSCR3 38604753- 38605663-38605744- Exc 0.922 0.634 −0.288 9.92E−45 38605662 38605743 38610760DTNBP1 15638036- 15651544- 15651595- Exc 0.963 0.855 −0.108 2.61E−0415651543 15651594 15652317 DTNBP1 15638036- 15651544- 15651640- Exc0.927 0.751 −0.176 9.68E−04 15651543 15651639 15652317 DUS2 68057255-68059318- 68059398- Unc 0.869 0.860 −0.009 9.16E−01 68059317 6805939768071908 DUSP11 73994031- 73994288- 73994335- Exc 0.981 0.659 −0.3229.71E−32 73994287 73994334 73996391 DUSP22 311963- 335114- 335164- Exc0.729 0.479 −0.250 9.80E−08 335113 335163 345853 DYNC2H1 103027500-103029406- 103029539- Exc 0.988 0.828 −0.160 3.48E−06 103029405103029538 103029638 EBPL 50237332- 50243913- 50243983- Exc 0.861 0.680−0.181 4.60E−04 50243912 50243982 50265389 EBPL 50235345- 50243913-50243983- Exc 0.743 0.441 −0.302 1.74E−04 50243912 50243982 50265389ECHDC2 53370506- 53370706- 53370763- Unc 0.889 0.882 −0.007 9.98E−0153370705 53370762 53373539 EDC3 74967484- 74979432- 74979521- Exc 0.1810.069 −0.112 6.98E−05 74979431 74979520 74988220 EDEM2 33719587-33721908- 33721959- Inc 0.134 0.409 0.276 6.98E−09 33721907 3372195833722540 EDRF1 127414408- 127417572- 127417674- Exc 0.713 0.348 −0.3654.46E−06 127417571 127417673 127417926 EFEMP1 56149583- 56150034-56150075- Inc 0.322 0.447 0.125  4.08E−106 56150033 56150074 56150845EHBP1 63206471- 63215066- 63215174- Exc 0.236 0.133 −0.103 3.49E−1363215065 63215173 63217850 EHBP1L1 65349437- 65351063- 65351237- Unc0.844 0.841 −0.004 8.14E−01 65351062 65351236 65351711 EHMT2 31856525-31856746- 31856848- Exc 0.894 0.761 −0.133 1.07E−04 31856745 3185684731857004 EIF4A2 186502486- 186502751- 186502891- Exc 0.760 0.622 −0.1384.02E−43 186502750 186502890 186503671 EIF4E2 233421241- 233422594-233422729- Exc 0.969 0.858 −0.111 1.51E−25 233422593 233422728 233428956EIF4G2 10822635- 10823208- 10823322- Unc 0.881 0.889 0.009 7.64E−0210823207 10823321 10823595 EIF4H 73604249- 73604577- 73604637- Inc 0.0820.194 0.113 1.21E−34 73604576 73604636 73609070 ELK1 47500875- 47509320-47509426- Exc 0.470 0.261 −0.209 2.18E−09 47509319 47509425 47509821ELMOD3 85598333- 85598563- 85598686- Unc 0.688 0.679 −0.009 9.08E−0185598562 85598685 85604466 ELMOD3 85582294- 85582678- 85582840- Unc0.747 0.738 −0.010 9.67E−01 85582677 85582839 85584089 ELN 73471044-73471970- 73472027- Exc 0.682 0.531 −0.151 2.07E−13 73471969 7347202673474215 ELN 73474378- 73474470- 73474515- Exc 0.989 0.821 −0.1674.96E−48 73474469 73474514 73474705 ELOVL1 43830680- 43830857- 43831048-Exc 0.954 0.841 −0.113 6.36E−25 43830856 43831047 43831234 EMC434520048- 34520630- 34520791- Unc 0.808 0.806 −0.001 9.68E−01 3452062934520790 34521953 EMC4 34520048- 34520638- 34520791- Unc 0.656 0.655−0.002 9.81E−01 34520637 34520790 34521953 ENC1 73932324- 73933390-73933527- Inc 0.108 0.356 0.248 7.14E−06 73933389 73933526 73936131 ENC173932324- 73933319- 73933444- Unc 0.133 0.128 −0.006 7.41E−01 7393331873933443 73936131 ENOSF1 677873- 678696- 678738- Exc 0.942 0.804 −0.1382.00E−05 678695 678737 683245 EP400 132446500- 132448077- 132448188- Unc0.220 0.214 −0.006 9.02E−01 132448076 132448187 132464241 EPB41L134806885- 34807683- 34807767- Exc 0.939 0.839 −0.101 6.57E−07 3480768234807766 34809785 EPB41L1 34802363- 34807683- 34807767- Exc 0.878 0.759−0.119 4.31E−04 34807682 34807766 34809785 EPB41L2 131191267- 131191468-131191522- Inc 0.302 0.713 0.411 1.34E−16 131191467 131191521 131197813EPS15L1 16472796- 16487933- 16488066- Unc 0.858 0.852 −0.006 9.33E−0116487932 16488065 16495939 ERBB2IP 65350780- 65370852- 65371059- Exc0.434 0.245 −0.190 2.48E−22 65370851 65371058 65372143 ERLEC1 54028980-54035436- 54035598- Exc 0.858 0.745 −0.112 5.82E−15 54035435 5403559754036350 ERMAP 43304593- 43305704- 43305725- Exc 0.981 0.830 −0.1511.04E−08 43305703 43305724 43305822 ERMARD 170151760- 170153383-170153469- Unc 0.103 0.108 0.005 8.37E−01 170153382 170153468 170153959ERMARD 170151760- 170153413- 170153469- Unc 0.103 0.108 0.005 8.37E−01170153412 170153468 170153959 ETHE1 44015719- 44030667- 44030812- Exc0.990 0.882 −0.108 1.26E−06 44030666 44030811 44031248 ETHE1 44015719-44030353- 44030502- Exc 0.853 0.637 −0.216 4.42E−20 44030352 4403050144030666 EVA1A 75749614- 75753238- 75753326- Unc 0.538 0.533 −0.0054.61E−01 75753237 75753325 75787805 EVC 5815890- 5819938- 5819982- Exc0.872 0.376 −0.496 1.54E−60 5819937 5819981 5825343 EVI5L 7920955-7921978- 7922011- Exc 0.676 0.479 −0.197 1.73E−05 7921977 79220107923076 FAM104A 71205908- 71208817- 71208880- Exc 0.310 0.197 −0.1131.25E−03 71208816 71208879 71223303 FAM111A 58910778- 58910970-58913330- Exc 0.900 0.699 −0.201 4.46E−04 58910969 58913329 58916308FAM114A1 38870168- 38879692- 38880048- Unc 0.898 0.906 0.008 6.74E−0138879691 38880047 38893363 FAM134C 40738910- 40739852- 40739883- Exc0.979 0.878 −0.101 1.32E−06 40739851 40739882 40744073 FAM13B 137354204-137354644- 137354836- Unc 0.861 0.861 0.001 1.00E+00 137354643 137354835137356719 FAM13B 137281687- 137281917- 137282001- Unc 0.874 0.874 0.0009.76E−01 137281916 137282000 137284643 FAM149B1 74994699- 74994951-74995077- Exc 0.927 0.795 −0.133 2.48E−04 74994950 74995076 74999069FAM160B2 21946810- 21947272- 21947366- Unc 0.101 0.108 0.007 8.30E−0121947271 21947365 21951950 FAM172A 93300229- 93386436- 93386537- Exc0.824 0.677 −0.147 1.92E−05 93386435 93386536 93388830 FAM172A 93388933-93410351- 93410475- Inc 0.644 0.790 0.146 5.58E−05 93410350 9341047493447215 FAM173A 771942- 772084- 772135- Unc 0.795 0.796 0.002 7.41E−01772083 772134 772308 FAM175A 84390305- 84391356- 84391550- Unc 0.8880.892 0.005 8.51E−01 84391355 84391549 84397795 FAM175A 84403398-84405145- 84405320- Unc 0.119 0.113 −0.005 8.75E−01 84405144 8440531984406138 FAM204A 120095936- 120101239- 120101440- Exc 0.583 0.449 −0.1341.38E−05 120101238 120101439 120101781 FAM208B 5773167- 5777267-5777510- Unc 0.816 0.807 −0.009 7.29E−01 5777266 5777509 5781580FAM211A- 16342729- 16342974- 16343018- Exc 0.279 0.155 −0.124  3.11E−100AS1 16342973 16343017 16343498 FAM211A- 16342729- 16342895- 16343018-Exc 0.313 0.180 −0.133  1.77E−110 AS1 16342894 16343017 16343498FAM211A- 16342729- 16342842- 16343018- Exc 0.328 0.179 −0.149  2.05E−136AS1 16342841 16343017 16343498 FAM21C 46268807- 46272721- 46272874- Inc0.421 0.663 0.243 1.76E−04 46272720 46272873 46274400 FAM35A 88930732-88935646- 88935853- Unc 0.737 0.743 0.006 9.25E−01 88935645 8893585288939831 FAM45A 120863710- 120864276- 120864535- Unc 0.655 0.664 0.0098.17E−01 120864275 120864534 120864822 FAP 163054251- 163054689-163054809- Exc 0.561 0.303 −0.258 4.88E−06 163054688 163054808 163055266FBXL12 9922394- 9923907- 9923951- Exc 0.170 0.025 −0.145 5.57E−079923906 9923950 9929220 FBXL3 77592858- 77595792- 77595997- Inc 0.7570.926 0.169 4.58E−04 77595791 77595996 77600961 FBXO25 381445- 382886-382936- Exc 0.840 0.715 −0.125 8.60E−05 382885 382935 385614 FBXW11171337802- 171341347- 171341410- Exc 0.474 0.318 −0.156 4.86E−05171341346 171341409 171433461 FBXW11 171337802- 171341347- 171341410-Exc 0.775 0.569 −0.206 2.10E−04 171341346 171341409 171423893 FDPS155278757- 155279544- 155279757- Unc 0.113 0.122 0.008 9.95E−01155279543 155279756 155279833 FGF5 81188334- 81196063- 81196167- Exc0.766 0.541 −0.225 8.66E−07 81196062 81196166 81207478 FGFR1 38286909-38287200- 38287467- Unc 0.906 0.899 −0.007 8.46E−01 38287199 3828746638314873 FGFR1OP 167424382- 167426996- 167427056- Inc 0.506 0.802 0.2953.12E−10 167426995 167427055 167435896 FHL2 106002998- 106013104-106013155- Exc 0.550 0.449 −0.101 1.22E−10 106013103 106013154 106015298FHOD3 33935609- 33952643- 33952708- Unc 0.902 0.893 −0.009 9.47E−0133952642 33952707 34081894 FIP1L1 54244091- 54245240- 54245285- Exc0.467 0.329 −0.138 4.26E−06 54245239 54245284 54245391 FIP1L1 54294351-54306749- 54306776- Exc 0.450 0.228 −0.223 2.87E−18 54306748 5430677554308819 FIP1L1 54257307- 54257597- 54257666- Inc 0.426 0.529 0.1045.19E−05 54257596 54257665 54265896 FLAD1 154961326- 154962036-154962184- Exc 0.922 0.744 −0.177 7.38E−05 154962035 154962183 154962634FLNA 153583441- 153585619- 153585643- Exc 0.631 0.481 −0.150 1.98E−91153585618 153585642 153585801 FLNB 58124257- 58127585- 58127657- Unc0.788 0.791 0.003 9.83E−01 58127584 58127656 58128376 FLNB 58124257-58127585- 58127624- Unc 0.710 0.709 −0.001 9.04E−01 58127584 5812762358128376 FN1 216244041- 216245534- 216245804- Exc 0.330 0.226 −0.1040.00E+00 216245533 216245803 216246934 FNBP1 132671279- 132678245-132678260- Unc 0.306 0.316 0.009 7.86E−01 132678244 132678259 132686122FNBP4 47746331- 47747289- 47747389- Inc 0.151 0.431 0.280 8.28E−1447747288 47747388 47752925 FNIP2 159754781- 159754953- 159755043- Exc0.722 0.580 −0.142 4.97E−06 159754952 159755042 159756556 FOSL165660768- 65661485- 65661593- Unc 0.889 0.887 −0.001 9.75E−01 6566148465661592 65664279 FOXN3 89647151- 89656731- 89656794- Exc 0.301 0.077−0.224 8.32E−15 89656730 89656793 89747293 FOXN3 89647151- 89656728-89656794- Exc 0.347 0.097 −0.250 1.19E−16 89656727 89656793 89747293FOXRED2 36897455- 36900145- 36900415- Unc 0.857 0.865 0.008 9.89E−0136900144 36900414 36900561 FRS2 69925837- 69931696- 69931764- Unc 0.1000.095 −0.006 9.70E−01 69931695 69931763 69955959 FRYL 48503751-48504845- 48504863- Inc 0.035 0.222 0.187 4.68E−08 48504844 4850486248507563 FUT8 66083092- 66083808- 66083910- Inc 0.006 0.234 0.2284.47E−59 66083807 66083909 66096209 FXR2 7495244- 7495389- 7495476- Inc0.020 0.152 0.132 1.28E−12 7495388 7495475 7495571 FYN 112101839-112167792- 112167833- Exc 0.877 0.741 −0.136 3.57E−07 112167791112167832 112194170 GAB1 144361536- 144378833- 144378923- Exc 0.4000.213 −0.187 2.06E−04 144378832 144378922 144380537 GABPB2 151070479-151076038- 151076152- Exc 0.702 0.490 −0.213 2.46E−04 151076037151076151 151079512 GABRE 151128449- 151129755- 151129838- Exc 0.1220.006 −0.116 4.60E−05 151129754 151129837 151130894 GALNS 88902676-88904030- 88904174- Exc 0.989 0.869 −0.120 2.92E−09 88904029 8890417388907399 GALNS 88908380- 88909114- 88909238- Exc 0.935 0.666 −0.2692.89E−11 88909113 88909237 88923165 GAS7 9862573- 9872994- 9873080- Unc0.871 0.876 0.005 4.60E−01 9872993 9873079 9885120 GBP3 89481098-89485809- 89485895- Unc 0.358 0.367 0.009 5.52E−01 89485808 8948589489486214 GBP3 89481098- 89485813- 89485895- Unc 0.234 0.225 −0.0097.69E−01 89485812 89485894 89486214 GEMIN8 14039631- 14044171- 14044341-Unc 0.696 0.687 −0.009 9.24E−01 14044170 14044340 14047895 GFPT2179728609- 179729423- 179729585- Exc 0.912 0.756 −0.156 9.65E−06179729422 179729584 179731771 GGCT 30538555- 30540152- 30540298- Inc0.755 0.964 0.209 2.33E−17 30540151 30540297 30544184 GIT2 110383155-110385061- 110385310- Exc 0.977 0.876 −0.101 4.89E−06 110385060110385309 110388971 GIT2 110385310- 110388972- 110389122- Inc 0.8220.946 0.124 1.00E−08 110388971 110389121 110390896 GK 30714801-30715849- 30715867- Exc 0.606 0.246 −0.360 1.00E−04 30715848 3071586630718530 GLIS3 4125942- 4286038- 4286524- Unc 0.807 0.808 0.001 8.26E−014286037 4286523 4299420 GLIS3 4118882- 4125734- 4125942- Unc 0.614 0.605−0.008 9.77E−01 4125733 4125941 4286037 GLRB 158065112- 158073870-158074163- Unc 0.754 0.752 −0.002 6.97E−01 158073869 158074162 158091583GLS 191778091- 191784941- 191784975- Exc 0.710 0.295 −0.414 1.11E−16191784940 191784974 191785749 GLS 191775048- 191777919- 191778091- Inc0.699 0.876 0.177 1.35E−06 191777918 191778090 191784940 GLT8D152734513- 52738740- 52738969- Unc 0.449 0.441 −0.009 5.89E−01 5273873952738968 52739462 GNAS 57470740- 57473996- 57474041- Unc 0.314 0.3160.003 7.51E−01 57473995 57474040 57478582 GNAS 57470740- 57473996-57474041- Unc 0.602 0.595 −0.006 4.76E−01 57473995 57474040 57478585GOLGA4 37396679- 37402734- 37402797- Exc 0.445 0.313 −0.132 4.72E−0637402733 37402796 37407570 GOLGB1 121437349- 121438493- 121438616- Exc0.523 0.340 −0.183 4.28E−05 121438492 121438615 121441108 GOLGB1121437349- 121438493- 121438601- Exc 0.519 0.326 −0.193 1.78E−05121438492 121438600 121441108 GOLT1B 21654883- 21661317- 21661496- Exc0.977 0.875 −0.101 1.30E−06 21661316 21661495 21665228 GPATCH8 42513914-42516039- 42516084- Unc 0.137 0.136 −0.002 9.47E−01 42516038 4251608342541839 GPBP1 56531860- 56532940- 56533000- Unc 0.223 0.231 0.0086.31E−01 56532939 56532999 56542126 GPR133 131621560- 131622189-131622775- Exc 0.972 0.837 −0.136 1.65E−07 131622188 131622774 131623712GPR180 95264645- 95271404- 95271585- Exc 0.676 0.385 −0.291 1.84E−0895271403 95271584 95271721 GRB10 50771606- 50778572- 50778688- Unc 0.2390.231 −0.007 9.10E−01 50778571 50778687 50823583 GRTPAP1 48853770-48854566- 48854593- Exc 0.992 0.878 −0.114 2.78E−07 48854565 4885459248855649 GTF2I 74157860- 74158478- 74158590- Inc 0.407 0.799 0.3928.75E−13 74158477 74158589 74159096 GTF2I 74131271- 74133198- 74133261-Inc 0.309 0.435 0.126 5.68E−11 74133197 74133260 74143123 GTF3A28004759- 28006868- 28006942- Exc 0.818 0.713 −0.105 5.18E−10 2800686728006941 28008275 GUF1 44696531- 44697632- 44697752- Exc 0.965 0.859−0.107 1.21E−04 44697631 44697751 44699424 GUSB 65439692- 65439906-65440059- Exc 0.567 0.435 −0.132 1.21E−04 65439905 65440058 65441001HACL1 15624497- 15626755- 15626850- Exc 0.868 0.550 −0.318 7.12E−0615626754 15626849 15628031 HAUS7 152719967- 152720335- 152720512- Exc0.465 0.347 −0.119 9.05E−04 152720334 152720511 152720999 HCFC1R13073363- 3073475- 3073532- Exc 0.922 0.794 −0.128 8.08E−07 30734743073531 3073847 HDAC10 50685396- 50686121- 50686206- Exc 0.741 0.534−0.207 7.53E−05 50686120 50686205 50686318 HDAC7 48189551- 48189689-48189800- Exc 0.465 0.218 −0.247 1.91E−13 48189688 48189799 48189989HDAC9 18633653- 18668973- 18669105- Unc 0.509 0.518 0.009 9.69E−0118668972 18669104 18674249 HECTD3 45475356- 45475658- 45475794- Exc0.929 0.801 −0.128 8.69E−06 45475657 45475793 45475872 HER3 89591404-89597369- 89597393- Exc 0.804 0.430 −0.374 8.53E−19 89597368 8959739289597484 HIPK3 33369560- 33369712- 33369775- Exc 0.190 0.084 −0.1053.69E−06 33369711 33369774 33370067 HMCN1 186143775- 186147548-186147899- Unc 0.589 0.585 −0.003 8.17E−01 186147547 186147898 186151299HMGXB4 35659868- 35659975- 35660090- Exc 0.335 0.200 −0.135 4.79E−0435659974 35660089 35660640 HNRNPA2B1 26230081- 26230613- 26230749- Inc0.761 0.874 0.113 3.95E−08 26230612 26230748 26232114 HNRNPD 83276555-83277690- 83277837- Exc 0.452 0.346 −0.106 7.97E−15 83277689 8327783683277948 HNRNPDL 83346037- 83346716- 83346821- Inc 0.187 0.302 0.1152.19E−16 83346715 83346820 83347189 HNRNPK 86588315- 86588817- 86588889-Unc 0.894 0.893 −0.001 8.03E−01 86588816 86588888 86589431 HPS1100193849- 100195029- 100195172- Exc 0.900 0.795 −0.105 1.72E−08100195028 100195171 100195391 HSCB 29139967- 29140603- 29140698- Unc0.869 0.864 −0.006 9.85E−01 29140602 29140697 29147228 HSD17B4118792064- 118807331- 118807396- Inc 0.022 0.619 0.597  5.07E−105118807330 118807395 118809602 HSF2 122744832- 122749048- 122749102- Inc0.256 0.583 0.328 1.59E−12 122749047 122749101 122752574 HUWE1 53652220-53652747- 53652990- Exc 0.384 0.270 −0.114 3.10E−05 53652746 5365298953654360 IFT88 21157159- 21163950- 21164007- Exc 0.845 0.579 −0.2664.98E−06 21163949 21164006 21165105 IGF2BP2 185376198- 185390329-185390458- Exc 0.643 0.384 −0.258 1.12E−16 185390328 185390457 185393083IL15RA 6002531- 6005706- 6005802- Inc 0.493 0.782 0.289 1.07E−03 60057056005801 6008107 1L15RA 6002531- 6005706- 6005805- Inc 0.571 0.825 0.2547.29E−04 6005705 6005804 6008107 IL17RA 17586493- 17586743- 17586845-Unc 0.834 0.841 0.008 7.57E−01 17586742 17586844 17588616 IL17RC9974388- 9974504- 9974543- Unc 0.575 0.582 0.007 9.92E−01 99745039974542 9974636 IL6 22766901- 22767132- 22767254- Unc 0.899 0.895 −0.0036.25E−01 22767131 22767253 22768311 INF2 105181194- 105181621-105181678- Inc 0.599 0.732 0.133 3.41E−05 105181620 105181677 105185131ING4 6760552- 6761437- 6761476- Exc 0.993 0.866 −0.128 1.40E−09 67614366761475 6761827 INO80E 30012362- 30012786- 30012852- Inc 0.539 0.8280.289 8.16E−06 30012785 30012851 30016541 INO80E 30012362- 30012533-30015979- Inc 0.562 0.819 0.258 1.08E−04 30012532 30015978 30016541INO80E 30012362- 30012533- 30012852- Inc 0.702 0.902 0.201 4.35E−0630012532 30012851 30016541 INO80E 30012362- 30012735- 30012852- Inc0.794 0.942 0.148 2.03E−07 30012734 30012851 30016541 INPP1 191208688-191224372- 191224425- Inc 0.091 0.224 0.133 5.46E−04 191224371 191224424191224764 INTS9 28695294- 28704264- 28704327- Unc 0.832 0.830 −0.0029.06E−01 28704263 28704326 28707729 IP6K2 48731674- 48731892- 48731959-Inc 0.134 0.552 0.419 6.60E−13 48731891 48731958 48732522 IP6K248731674- 48732127- 48732258- Unc 0.290 0.296 0.006 8.95E−01 4873212648732257 48732522 IPOS 30833573- 30834593- 30834752- Exc 0.993 0.892−0.101 9.08E−09 30834592 30834751 30837234 IQCB1 121545028- 121547317-121547480- Inc 0.705 0.868 0.163 7.90E−04 121547316 121547479 121547707IRAK4 44162076- 44165023- 44165169- Exc 0.554 0.239 −0.315 4.03E−0844165022 44165168 44165982 ISOC2 55966698- 55967003- 55967213- Exc 0.8750.761 −0.115 1.01E−06 55967002 55967212 55967715 IST1 71956584-71957191- 71957284- Exc 0.951 0.805 −0.146 5.81E−27 71957190 7195728371958671 ITGB1BP1 9558862- 9560119- 9560230- Inc 0.310 0.522 0.2123.37E−10 9560118 9560229 9562607 KANSL3 97285282- 97285409- 97285500-Unc 0.889 0.892 0.003 9.79E−01 97285408 97285499 97297048 KAT6A41906821- 41907138- 41907226- Unc 0.182 0.186 0.005 9.37E−01 4190713741907225 41909418 KATNBL1 34455892- 34470022- 34470201- Inc 0.077 0.2190.142 3.89E−05 34470021 34470200 34502151 KCTD20 36438035- 36442566-36442840- Unc 0.899 0.893 −0.006 6.98E−01 36442565 36442839 36446897KDM4C 7103871- 7105402- 7105501- Exc 0.174 0.022 −0.152 7.90E−05 71054017105500 7128065 KDM5A 394829- 395292- 395374- Inc 0.301 0.443 0.1433.33E−04 395291 395373 401924 KIAA0100 26960770- 26960913- 26961105- Exc0.975 0.850 −0.125 1.28E−22 26960912 26961104 26961534 KIAA0232 6873410-6878387- 6878485- Unc 0.894 0.885 −0.009 6.15E−01 6878386 68784846882513 KIAA0368 114213836- 114235177- 114235281- Unc 0.809 0.813 0.0038.91E−01 114235176 114235280 114246264 KIAA0753 6526892- 6528075-6528182- Unc 0.857 0.858 0.001 8.05E−01 6528074 6528181 6531436 KIAA155132113806- 32123123- 32123291- Unc 0.893 0.898 0.005 9.29E−01 3212312232123290 32133811 KIAA1586 56912195- 56915572- 56915653- Unc 0.866 0.863−0.003 9.48E−01 56915571 56915652 56917483 KIAA1731 93454579- 93455120-93455217- Unc 0.833 0.838 0.005 9.89E−01 93455119 93455216 93456206KIF3A 132039312- 132042143- 132042152- Exc 0.525 0.260 −0.265 3.02E−06132042142 132042151 132046650 KIFC3 57806201- 57819376- 57819579- Unc0.168 0.165 −0.003 9.58E−01 57819375 57819578 57828910 KIFC3 57806201-57824842- 57824979- Unc 0.109 0.104 −0.005 9.03E−01 57824841 5782497857828910 KITLG 88900915- 88909311- 88909395- Exc 0.985 0.884 −0.1012.32E−16 88909310 88909394 88910110 KLC1 104145883- 104151323-104151374- Exc 0.286 0.176 −0.110 1.43E−06 104151322 104151373 104153417KLC1 104153549- 104158696- 104158763- Inc 0.330 0.755 0.425 1.93E−42104158695 104158762 104166991 KLHL12 202861788- 202862367- 202862554-Unc 0.855 0.860 0.005 9.23E−01 202862366 202862553 202863311 KTN156128331- 56130673- 56130760- Inc 0.268 0.525 0.257 7.38E−64 5613067256130759 56133958 KTN1 56139731- 56139890- 56139974- Inc 0.387 0.4950.108 4.17E−12 56139889 56139973 56142552 KTN1 56047073- 56068475-56068599- Unc 0.410 0.406 −0.004 9.19E−01 56068474 56068598 56078736L3HYPDH 59939809- 59941157- 59941245- Inc 0.197 0.344 0.147 4.42E−0659941156 59941244 59942586 LACC1 44463119- 44464250- 44464411- Exc 0.9250.789 −0.136 1.91E−05 44464249 44464410 44465584 LAMTOR3 100813192-100815112- 100815158- Exc 0.890 0.750 −0.140 9.62E−12 100815111100815157 100815491 LAS1L 64744143- 64744444- 64744495- Exc 0.214 0.004−0.210 4.86E−12 64744443 64744494 64744844 LBR 225594535- 225597993-225598119- Unc 0.885 0.885 0.000 9.73E−01 225597992 225598118 225599038LDB2 16504497- 16507463- 16507606- Unc 0.623 0.618 −0.006 8.46E−0116507462 16507605 16510157 LENG8 54963932- 54964725- 54964836- Exc 0.8990.779 −0.120 1.85E−19 54964724 54964835 54965608 LETMD1 51442969-51445875- 51445991- Exc 0.439 0.207 −0.232 2.76E−10 51445874 5144599051450132 LETMD1 51442969- 51449927- 51450029- Exc 0.516 0.214 −0.3021.21E−17 51449926 51450028 51450132 LETMD1 51442969- 51445875- 51445991-Exc 0.872 0.524 −0.348 4.96E−10 51445874 51445990 51449617 LETMD151442969- 51447561- 51447644- Exc 0.904 0.512 −0.392 1.12E−15 5144756051447643 51449617 LETMD1 51442969- 51447595- 51447644- Exc 0.909 0.511−0.398 1.35E−16 51447594 51447643 51449617 LGALS8 236706088- 236706215-236706341- Inc 0.243 0.408 0.165 7.61E−08 236706214 236706340 236706859LINC00963 132251579- 132255695- 132255875- Exc 0.837 0.709 −0.1288.09E−04 132255694 132255874 132265601 LMAN2L 97377763- 97399256-97399339- Exc 0.956 0.849 −0.108 1.64E−05 97399255 97399338 97400145LMAN2L 97400264- 97402874- 97402955- Inc 0.049 0.228 0.179 2.48E−0697402873 97402954 97403685 LMO7 76210863- 76287318- 76287389- Exc 0.7610.597 −0.164 5.14E−38 76287317 76287388 76301164 LONRF1 12594650-12594781- 12594870- Inc 0.005 0.243 0.239 7.33E−11 12594780 1259486912595503 LOXL3 74763599- 74763836- 74764056- Exc 0.907 0.751 −0.1561.95E−05 74763835 74764055 74776495 LPHN2 82451040- 82452973- 82453026-Exc 0.469 0.362 −0.107 4.04E−04 82452972 82453025 82456074 LPHN282451040- 82452944- 82453026- Exc 0.413 0.261 −0.152 2.47E−06 8245294382453025 82456074 LPHN2 82417827- 82418671- 82418710- Inc 0.193 0.4550.263 1.56E−19 82418670 82418709 82421560 LPIN1 11913872- 11916212-11916320- Inc 0.118 0.532 0.414 4.79E−35 11916211 11916319 11919644LRCH3 197581317- 197585705- 197585777- Inc 0.352 0.633 0.281 1.38E−12197585704 197585776 197592293 LRP12 105521303- 105544135- 105544192- Unc0.738 0.739 0.002 9.98E−01 105544134 105544191 105601046 LRRC2899796331- 99816781- 99816822- Exc 0.764 0.347 −0.417 1.41E−23 9981678099816821 99827461 LRRC32 76369079- 76370627- 76372553- Exc 0.939 0.838−0.101 2.33E−04 76370626 76372552 76376914 LSM1 38021359- 38027320-38027436- Inc 0.827 0.957 0.130 2.13E−27 38027319 38027435 38029482LTA4H 96396843- 96397616- 96397760- Exc 0.864 0.762 −0.103 6.37E−0596397615 96397759 96400091 LTBP1 33540337- 33567905- 33568031- Exc 0.9470.834 −0.114 1.40E−16 33567904 33568030 33572433 LTBP3 65307353-65307484- 65307625- Exc 0.663 0.325 −0.338 3.24E−05 65307483 6530762465307715 LTBP4 41128573- 41128855- 41128927- Exc 0.869 0.723 −0.1475.23E−04 41128854 41128926 41129508 LUC7L 258188- 258600- 258664- Exc0.196 0.001 −0.195 5.16E−33 258599 258663 270647 LUC7L 277336- 278332-278402- Exc 0.388 0.003 −0.385 4.67E−27 278331 278401 279277 LYPLAL1219352589- 219366424- 219366594- Exc 0.949 0.848 −0.101 5.35E−04219366423 219366593 219383873 LYRM7 130517993- 130522721- 130522803- Exc0.934 0.750 −0.184 5.86E−05 130522720 130522802 130535223 LZTFL145877277- 45879419- 45879544- Exc 0.856 0.727 −0.129 1.28E−03 4587941845879543 45883480 MACF1 39929359- 39930767- 39930785- Exc 0.611 0.503−0.108 1.71E−07 39930766 39930784 39934286 MACF1 39715776- 39717518-39717614- Inc 0.005 0.126 0.121 3.68E−08 39717517 39717613 39719969 MADD47291302- 47295378- 47295528- Exc 0.989 0.788 −0.201 1.89E−04 4729537747295527 47296113 MADD 47346129- 47348289- 47348359- Unc 0.883 0.8870.005 9.39E−01 47348288 47348358 47350208 MAGOHB 10763280- 10765239-10765578- Inc 0.098 0.210 0.111 6.40E−04 10765238 10765577 10766037MAGOHB 10760536- 10761697- 10761983- Inc 0.140 0.249 0.109 4.64E−0610761696 10761982 10762429 MAN2C1 75654795- 75654983- 75655090- Exc0.899 0.652 −0.247 3.24E−12 75654982 75655089 75656828 MAP2K5 67995747-68020254- 68020284- Unc 0.835 0.842 0.007 7.64E−01 68020253 6802028368040568 MAP3K3 61769223- 61769602- 61769780- Exc 0.933 0.803 −0.1302.79E−11 61769601 61769779 61770908 MAP4K4 102486878- 102487956-102488148- Exc 0.453 0.327 −0.126 1.29E−18 102487955 102488147 102490108MAP7D1 36639080- 36640499- 36640610- Unc 0.666 0.668 0.002 9.54E−0136640498 36640609 36641799 MAPK11 50705912- 50705998- 50706057- Exc0.972 0.797 −0.175 6.33E−04 50705997 50706056 50706248 MAPK12 50685396-50686121- 50686206- Exc 0.741 0.534 −0.207 7.53E−05 50686120 5068620550686318 MAPK9 179707609- 179713975- 179714068- Unc 0.198 0.200 0.0019.40E−01 179713974 179714067 179718847 MAPKAP1 128246863- 128268589-128268697- Inc 0.571 0.683 0.112 9.36E−08 128268588 128268696 128305337MARK3 103964866- 103966493- 103966538- Inc 0.538 0.737 0.199 3.24E−16103966492 103966537 103969218 MARK3 103958372- 103966493- 103966538- Inc0.758 0.880 0.122 1.67E−04 103966492 103966537 103969218 MAZ 29820063-29820861- 29821086- Unc 0.160 0.165 0.005 8.90E−01 29820860 2982108529821397 MBD1 47799326- 47799704- 47799842- Unc 0.848 0.858 0.0107.89E−01 47799703 47799841 47799933 MBD5 148779254- 148811960-148812019- Exc 0.267 0.017 −0.250 2.05E−06 148811959 148812018 148936268MBNL1 152165563- 152173331- 152173367- Inc 0.612 0.771 0.159 6.22E−15152173330 152173366 152174055 MBOAT2 9000895- 9002720- 9002853- Exc0.993 0.819 −0.174 3.07E−22 9002719 9002852 9004299 MBOAT2 9000895-9002401- 9002453- Exc 0.949 0.296 −0.653 6.20E−17 9002400 90024529004299 MCCC2 70900296- 70922467- 70922581- Unc 0.850 0.845 −0.0059.93E−01 70922466 70922580 70927947 ME3 86161441- 86168408- 86168802-Inc 0.222 0.453 0.231 1.78E−04 86168407 86168801 86176132 MECR 29543198-29547350- 29547434- Unc 0.195 0.195 0.000 9.67E−01 29547349 2954743329557242 MED13 60032929- 60033041- 60033200- Exc 0.975 0.819 −0.1561.34E−14 60033040 60033199 60033699 MED15 20922919- 20929400- 20929520-Exc 0.596 0.429 −0.167 7.19E−05 20929399 20929519 20936897 MED23131931387- 131936464- 131936482- Unc 0.210 0.217 0.007 9.45E−01131936463 131936481 131937046 MEG3 101297872- 101298849- 101298979- Exc0.273 0.138 −0.135 1.15E−09 101298848 101298978 101302503 MEG3101296087- 101298849- 101298979- Exc 0.654 0.482 −0.172 6.45E−05101298848 101298978 101302503 MEG3 101297872- 101302076- 101302217- Exc0.660 0.431 −0.229 5.34E−23 101302075 101302216 101302503 MEG3101297872- 101302073- 101302217- Exc 0.659 0.428 −0.232 2.36E−23101302072 101302216 101302503 MEG3 101296087- 101297758- 101297872- Inc0.606 0.798 0.192 3.43E−14 101297757 101297871 101298848 MEGF6 3415391-3415702- 3415831- Exc 0.752 0.480 −0.271 1.38E−06 3415701 34158303416151 MEGF6 3413348- 3413552- 3413684- Exc 0.622 0.264 −0.358 3.37E−123413551 3413683 3413796 MEGF6 3407524- 3409203- 3409332- Unc 0.852 0.8600.008 3.46E−01 3409202 3409331 3410334 MEIS1 66795889- 66796182-66796278- Unc 0.654 0.655 0.002 3.87E−01 66796181 66796277 66798377METAP1 99917019- 99926920- 99927018- Inc 0.022 0.202 0.179 7.38E−1499926919 99927017 99950017 METAP1 99917019- 99926920- 99927022- Inc0.011 0.126 0.114 4.21E−09 99926919 99927021 99950017 METTL10 126449073-126450869- 126451128- Unc 0.492 0.482 −0.010 8.27E−01 126450868126451127 126453960 METTL14 119625207- 119626766- 119626977- Exc 0.8960.795 −0.102 8.30E−04 119626765 119626976 119631152 METTL21A 208478168-208485365- 208485419- Unc 0.142 0.135 −0.007 8.61E−01 208485364208485418 208486529 MFF 228205097- 228207461- 228207536- Exc 0.326 0.185−0.141 1.63E−11 228207460 228207535 228211941 MFF 228190144- 228195342-228195563- Exc 0.902 0.752 −0.150 4.68E−17 228195341 228195562 228197134MFF 228205097- 228211942- 228212101- Exc 0.851 0.689 −0.162 1.35E−17228211941 228212100 228217229 MFF 228190144- 228193394- 228195563- Exc0.914 0.743 −0.171 3.75E−23 228193393 228195562 228197134 MFF 228205097-228207461- 228207536- Exc 0.378 0.171 −0.206 1.50E−12 228207460228207535 228220392 MFF 228190144- 228193394- 228193506- Exc 0.836 0.448−0.387 1.16E−33 228193393 228193505 228195341 MFF 228193506- 228194322-228194500- Inc 0.091 0.196 0.104 3.48E−05 228194321 228194499 228195341MFSD12 3546167- 3546253- 3546424- Exc 0.952 0.836 −0.117 1.26E−063546252 3546423 3547269 MGEA5 103552701- 103553670- 103553756- Exc 0.9210.814 −0.107 2.90E−10 103553669 103553755 103557736 MGLL 127414034-127429419- 127429509- Unc 0.893 0.892 −0.002 8.74E−01 127429418127429508 127439895 MGST2 140587232- 140599697- 140599797- Exc 0.9420.729 −0.213 1.98E−06 140599696 140599796 140616350 MICU3 16921747-16927197- 16927229- Unc 0.814 0.806 −0.008 8.50E−01 16927196 1692722816935291 MINK1 4795530- 4795697- 4795808- Exc 0.424 0.289 −0.1347.35E−05 4795696 4795807 4795950 MIR22HG 1617309- 1617665- 1617748- Exc0.817 0.649 −0.168 3.76E−05 1617664 1617747 1619423 MKNK2 2037829-2039630- 2039856- Unc 0.552 0.545 −0.007 4.92E−01 2039629 20398552040132 MKS1 56291749- 56292102- 56292200- Exc 0.973 0.797 −0.1764.57E−04 56292101 56292199 56293448 MLF1 158289181- 158310223-158310371- Exc 1.000 0.824 −0.176 2.77E−04 158310222 158310370 158314650MLH1 37053591- 37055923- 37056036- Exc 1.000 0.890 −0.110 1.29E−1037055922 37056035 37058996 MLH1 37053591- 37055923- 37056036- Exc 0.9820.802 −0.179 1.88E−07 37055922 37056035 37061800 MLLT10 21827842-21846550- 21846754- Unc 0.212 0.204 −0.008 9.92E−01 21846549 2184675321875222 MLLT6 36877001- 36878131- 36878481- Exc 0.838 0.636 −0.2023.61E−04 36878130 36878480 36878930 MLST8 2257347- 2258211- 2258336- Exc0.881 0.640 −0.241 1.01E−18 2258210 2258335 2258450 MMP19 56234667-56234890- 56235021- Exc 0.952 0.743 −0.209 2.66E−07 56234889 5623502056236136 MMP19 56234667- 56234890- 56234992- Exc 0.920 0.626 −0.2932.11E−06 56234889 56234991 56236136 MORF4L2 102933529- 102939609-102939658- Exc 0.154 0.053 −0.101 8.00E−52 102939608 102939657 102940098MORF4L2 102933580- 102939609- 102939658- Exc 0.385 0.203 −0.183 8.78E−18102939608 102939657 102940098 MORF4L2 102933549- 102939609- 102939658-Exc 0.597 0.281 −0.316 1.77E−28 102939608 102939657 102940098 MOSPD1134031065- 134033120- 134033196- Exc 0.971 0.832 −0.139 1.45E−09134033119 134033195 134033309 MOSPD1 134023223- 134025509- 134025671-Inc 0.625 0.832 0.207 1.93E−09 134025508 134025670 134030846 MPDZ13183585- 13186269- 13186386- Exc 0.894 0.770 −0.124 4.45E−07 1318626813186385 13188782 MPI 75188667- 75189352- 75189561- Exc 0.908 0.800−0.107 1.24E−04 75189351 75189560 75189852 MPPE1 11897356- 11897525-11897620- Unc 0.416 0.424 0.008 9.19E−01 11897524 11897619 11906201MPV17 27535640- 27535861- 27536022- Exc 0.916 0.811 −0.106 2.99E−0727535860 27536021 27545314 MRI1 13875924- 13876768- 13876944- Unc 0.6920.700 0.008 9.25E−01 13876767 13876943 13879172 MRI1 13875924- 13876768-13876880- Unc 0.604 0.611 0.007 9.69E−01 13876767 13876879 13879172MRPL33 27995560- 27997291- 27997398- Exc 0.447 0.291 −0.156 3.59E−2827997290 27997397 28002299 MRPL55 228296020- 228296138- 228296176- Unc0.278 0.270 −0.008 9.35E−01 228296137 228296175 228296655 MRPL55228296020- 228296138- 228296210- Unc 0.243 0.235 −0.008 9.55E−01228296137 228296209 228296655 MSRB3 65672646- 65702309- 65702436- Exc0.521 0.420 −0.101 1.46E−04 65702308 65702435 65720605 MSRB3 65672646-65700643- 65700807- Inc 0.140 0.290 0.149 1.45E−04 65700642 6570080665702308 MTCH2 47656287- 47657097- 47657124- Exc 0.915 0.813 −0.1022.02E−16 47657096 47657123 47660250 MTIF2 55491002- 55493517- 55493655-Unc 0.163 0.155 −0.008 6.61E−01 55493516 55493654 55494704 MTMR295598841- 95620776- 95620849- Exc 0.262 0.122 −0.141 3.54E−05 9562077595620848 95621319 MTMR2 95621426- 95647406- 95647477- Inc 0.506 0.6790.173 8.49E−04 95647405 95647476 95657038 MTMR3 30416874- 30418018-30418129- Exc 0.810 0.641 −0.169 6.23E−06 30418017 30418128 30418597MTMR3 30418687- 30419446- 30419473- Exc 0.384 0.214 −0.169 3.78E−0630419445 30419472 30421618 MTMR6 25823631- 25825787- 25825914- Exc 0.9340.675 −0.259 7.28E−27 25825786 25825913 25825990 MTRR 7871037- 7873486-7873640- Exc 0.770 0.468 −0.302 2.38E−12 7873485 7873639 7875370 MTRR7871037- 7873486- 7873626- Exc 0.625 0.288 −0.336 1.13E−09 78734857873625 7875370 MTSS1L 70712313- 70713218- 70713227- Exc 0.308 0.193−0.115 6.64E−12 70713217 70713226 70713532 MXI1 111988080- 112004586-112004632- Unc 0.892 0.898 0.006 9.46E−01 112004585 112004631 112038937MXRA7 74676962- 74679929- 74680010- Unc 0.158 0.165 0.007 3.84E−0174679928 74680009 74681153 MYBL1 67477061- 67478299- 67478479- Exc 0.2430.053 −0.190 9.27E−05 67478298 67478478 67478918 MYCBP2 77699604-77700453- 77700678- Exc 0.898 0.773 −0.125 4.67E−06 77700452 7770067777713330 MYCBP2 77673149- 77692475- 77692655- Unc 0.215 0.207 −0.0078.24E−01 77692474 77692654 77695507 MYEF2 48441569- 48443297- 48443369-Inc 0.369 0.722 0.353 1.36E−04 48443296 48443368 48443669 MYLK123444926- 123451743- 123451950- Exc 0.802 0.611 −0.191 4.65E−34123451742 123451949 123452533 MYLK 123550518- 123554715- 123554783- Inc0.244 0.589 0.345 1.49E−21 123554714 123554782 123595405 MYLK 123550518-123595406- 123595465- Inc 0.739 0.897 0.158 1.79E−05 123595405 123595464123603052 MYNN 169500432- 169501265- 169501349- Exc 0.805 0.625 −0.1812.38E−05 169501264 169501348 169502409 MYNN 169491251- 169491819-169491886- Inc 0.186 0.328 0.142 7.51E−05 169491818 169491885 169492052MYO18A 27442859- 27443462- 27443474- Inc 0.106 0.359 0.253 2.29E−0727443461 27443473 27445062 MYO18A 27449272- 27464034- 27464103- Unc0.324 0.330 0.005 7.92E−01 27464033 27464102 27467357 MYO19 34870392-34870956- 34871026- Exc 0.980 0.870 −0.109 9.03E−04 34870955 3487102534871700 MYO1B 192265195- 192267358- 192267445- Inc 0.293 0.483 0.1903.03E−41 192267357 192267444 192272840 MYO1B 192265195- 192265475-192265562- Inc 0.169 0.296 0.128 2.28E−11 192265474 192265561 192267357MYO5A 52628754- 52630007- 52630082- Exc 0.180 0.063 −0.118 5.42E−0552630006 52630081 52632392 MYO5A 52638659- 52641015- 52641024- Inc 0.8230.953 0.130 1.78E−04 52641014 52641023 52643450 MYO5A 52632592-52635314- 52635395- Unc 0.610 0.617 0.007 9.78E−01 52635313 5263539452638557 N6AMT2 21306261- 21311862- 21311945- Unc 0.745 0.755 0.0109.61E−01 21311861 21311944 21331593 NABP1 192546744- 192547218-192547322- Inc 0.531 0.729 0.198 2.10E−25 192547217 192547321 192548454NADK2 36207368- 36208727- 36208793- Exc 0.107 0.005 −0.102 2.64E−1136208726 36208792 36211945 NAE1 66860487- 66860580- 66860684- Exc 0.9740.859 −0.115 2.65E−09 66860579 66860683 66864749 NAE1 66860487-66860571- 66860684- Exc 0.912 0.596 −0.315 1.31E−08 66860570 6686068366864749 NBN 90993752- 90994181- 90994231- Exc 0.173 0.017 −0.1569.26E−10 90994180 90994230 90994949 NCK2 106471746- 106497784-106498506- Unc 0.595 0.586 −0.008 9.98E−01 106497783 106498505 106509437NCOR2 124810917- 124811955- 124812180- Unc 0.657 0.657 0.000 9.08E−01124811954 124812179 124815390 NCOR2 124810917- 124812093- 124812180- Unc0.682 0.681 −0.001 9.02E−01 124812092 124812179 124815390 NEDD197301403- 97301480- 97301635- Unc 0.870 0.878 0.008 9.75E−01 9730147997301634 97303529 NEDD1 97301079- 97301382- 97301635- Unc 0.829 0.826−0.003 9.29E−01 97301381 97301634 97303529 NEK1 170506701- 170508710-170508765- Exc 0.982 0.830 −0.152 4.60E−07 170508709 170508764 170509799NEO1 73566347- 73567033- 73567066- Inc 0.029 0.149 0.120 6.18E−0973567032 73567065 73570471 NEXN 78383959- 78390873- 78390915- Exc 0.7920.654 −0.138 1.27E−08 78390872 78390914 78392098 NF2 30077591- 30079009-30079069- Inc 0.564 0.807 0.244 4.92E−09 30079008 30079068 30090740 NF230077591- 30079009- 30079054- Inc 0.733 0.900 0.167 1.66E−10 3007900830079053 30090740 NFE2L1 46133961- 46134394- 46134484- Exc 0.483 0.327−0.156 1.37E−34 46134393 46134483 46134705 NIN 51230683- 51233025-51233115- Unc 0.888 0.896 0.008 8.80E−01 51233024 51233114 51233497NIPA2 23021430- 23033278- 23033414- Exc 0.771 0.608 −0.163 9.71E−0423033277 23033413 23033893 NIPA2 23021430- 23027801- 23027923- Exc 0.5110.326 −0.185 1.06E−05 23027800 23027922 23033277 NLRC5 57108596-57110731- 57110815- Exc 0.979 0.857 −0.122 1.51E−05 57110730 5711081457111207 NLRX1 119042183- 119043065- 119043135- Exc 0.885 0.742 −0.1431.09E−03 119043064 119043134 119043609 NPEPPS 45646861- 45654447-45654527- Inc 0.036 0.172 0.135 4.25E−07 45654446 45654526 45656755 NPR235802605- 35802729- 35802801- Exc 0.979 0.878 −0.101 2.79E−11 3580272835802800 35805507 NPRL3 162775- 167300- 167375- Exc 0.852 0.697 −0.1551.74E−05 167299 167374 169124 NPRL3 169255- 174936- 175073- Unc 0.2010.206 0.006 9.15E−01 174935 175072 180520 NPRL3 162775- 180521- 180591-Unc 0.856 0.858 0.003 9.12E−01 180520 180590 188148 NRG1 32617925-32620736- 32620878- Inc 0.328 0.510 0.182 1.86E−07 32620735 3262087732621265 NSFL1C 1435778- 1436359- 1436516- Exc 0.337 0.214 −0.1233.38E−07 1436358 1436515 1438844 NSFL1C 1435778- 1436359- 1436365- Exc0.498 0.345 −0.153 1.50E−10 1436358 1436364 1438844 NSMCE2 126163520-126168242- 126168341- Inc 0.029 0.162 0.133 3.75E−10 126168241 126168340126194344 NSUN4 46810817- 46812593- 46812748- Exc 0.941 0.817 −0.1248.10E−04 46812592 46812747 46818539 NT5C2 104865559- 104871502-104871563- Exc 0.657 0.351 −0.306 4.94E−05 104871501 104871562 104899162NTMT1 132388575- 132394929- 132395081- Unc 0.837 0.828 −0.009 8.12E−01132394928 132395080 132396332 NTPCR 233086491- 233091303- 233091466- Unc0.776 0.785 0.009 8.51E−01 233091302 233091465 233092092 NUB1 151042553-151046159- 151046327- Exc 0.984 0.858 −0.126 3.03E−19 151046158151046326 151048509 NUBP2 1836657- 1836758- 1836957- Unc 0.569 0.5750.006 7.28E−01 1836757 1836956 1837677 NUMB 73822475- 73833605-73833690- Unc 0.700 0.697 −0.003 8.55E−01 73833604 73833689 73876644NUP43 150057759- 150059779- 150059915- Exc 0.983 0.865 −0.118 7.07E−08150059778 150059914 150063525 NUP62 50413142- 50430951- 50431106- Inc0.662 0.787 0.124 1.01E−03 50430950 50431105 50432582 NUP98 3704672-3707294- 3707425- Unc 0.872 0.862 −0.009 8.71E−01 3707293 37074243712576 NUPL2 23226766- 23235458- 23235535- Exc 0.846 0.602 −0.2444.56E−09 23235457 23235534 23236298 NUTF2 67880889- 67881181- 67881360-Unc 0.107 0.104 −0.003 9.22E−01 67881180 67881359 67899004 NUTM2A-AS189048253- 89067714- 89067818- Exc 0.220 0.100 −0.120 1.51E−07 8906771389067817 89086386 OARD1 41035177- 41036580- 41036693- Exc 0.830 0.563−0.267 6.53E−07 41036579 41036692 41037814 OCRL 128710530- 128718321-128718345- Inc 0.104 0.364 0.260 1.97E−18 128718320 128718344 128720978ODF2 131223290- 131231462- 131231633- Exc 0.974 0.872 −0.102 3.16E−04131231461 131231632 131233586 ODF2L 86820543- 86822127- 86822286- Exc0.786 0.514 −0.272 2.12E−07 86822126 86822285 86824469 OFD1 13780564-13781864- 13781975- Inc 0.850 0.981 0.131 7.32E−06 13781863 1378197413785245 OPN3 241761300- 241767722- 241767882- Unc 0.441 0.437 −0.0049.18E−01 241767721 241767881 241803183 OPTN 13150290- 13150962-13151016- Exc 0.341 0.121 −0.220 4.83E−19 13150961 13151015 13151111OPTN 13142303- 13150138- 13150290- Inc 0.210 0.387 0.176 8.72E−2413150137 13150289 13151111 ORMDL1 190647329- 190647740- 190647850- Exc0.702 0.407 −0.295 6.70E−15 190647739 190647849 190648994 OS9 58112966-58113882- 58114047- Exc 0.525 0.344 −0.181 3.42E−70 58113881 5811404658114188 OSBPL8 76844760- 76853639- 76853676- Inc 0.096 0.296 0.2005.73E−12 76853638 76853675 76881289 OSBPL8 76844769- 76853639- 76853676-Inc 0.078 0.269 0.191 2.58E−22 76853638 76853675 76881289 OSER1-AS142843644- 42846007- 42846323- Unc 0.153 0.153 0.000 8.79E−01 4284600642846322 42853460 P4HA2 131554338- 131562390- 131562915- Unc 0.162 0.155−0.007 7.05E−01 131562389 131562914 131563482 P4HA2 131554338-131562625- 131562915- Unc 0.167 0.160 −0.007 7.10E−01 131562624131562914 131563482 PACRGL 20715163- 20726431- 20726512- Exc 0.216 0.095−0.120 7.77E−05 20726430 20726511 20728907 PACRGL 20706438- 20709426-20709494- Exc 0.845 0.666 −0.179 1.22E−04 20709425 20709493 20714410PACRGL 20709494- 20711306- 20711397- Exc 0.805 0.563 −0.242 1.38E−0520711305 20711396 20714410 PACRGL 20706438- 20711306- 20711397- Exc0.767 0.462 −0.305 8.76E−06 20711305 20711396 20714410 PAM 102296934-102309820- 102310141- Exc 0.601 0.478 −0.123 4.07E−33 102309819102310140 102325975 PARD3 34690846- 34739245- 34739377- Exc 0.749 0.584−0.165 4.33E−06 34739244 34739376 34759012 PARD3 34620273- 34625127-34625172- Unc 0.809 0.805 −0.003 8.88E−01 34625126 34625171 34626205PARL 183551378- 183551512- 183551614- Exc 0.937 0.819 −0.118 1.42E−10183551511 183551613 183558357 PARP11 3935400- 3938076- 3938197- Exc0.495 0.250 −0.245 8.16E−04 3938075 3938196 3939055 PARP6 72542434-72543186- 72543299- Inc 0.705 0.870 0.164 2.78E−06 72543185 7254329872543547 PARP6 72542434- 72543186- 72543296- Inc 0.754 0.902 0.1481.76E−07 72543185 72543295 72543547 PATL1 59423214- 59423429- 59423519-Exc 0.878 0.710 −0.168 2.80E−12 59423428 59423518 59423971 PCBP253861078- 53861589- 53861628- Exc 0.649 0.431 −0.218  2.54E−160 5386158853861627 53862560 PCID2 113839875- 113845186- 113845290- Exc 0.973 0.757−0.217 1.52E−31 113845185 113845289 113849384 PCM1 17830197- 17838100-17838265- Exc 0.579 0.444 −0.135 4.45E−05 17838099 17838264 17842955PCNXL2 233344436- 233353645- 233353678- Exc 1.000 0.899 −0.101 1.52E−05233353644 233353677 233353776 PCNXL2 233152901- 233160892- 233161146-Unc 0.882 0.891 0.009 9.04E−01 233160891 233161145 233190013 PCNXL460559138- 60574304- 60575046- Exc 0.648 0.498 −0.151 3.73E−06 6057430360575045 60581417 PCYT2 79863031- 79863258- 79863324- Exc 0.954 0.804−0.150 4.38E−10 79863257 79863323 79863545 PDE4DIP 144857729- 144859759-144859999- Inc 0.682 0.821 0.140 6.83E−07 144859758 144859998 144863317PDGFC 157771569- 157782581- 157782642- Unc 0.135 0.141 0.006 9.73E−01157782580 157782641 157891937 PDLIM2 22447255- 22449064- 22449182- Exc0.864 0.542 −0.322  9. ISE−124 22449063 22449181 22451245 PDP1 94929308-94930139- 94930174- Unc 0.185 0.184 −0.002 8.92E−01 94930138 9493017394934243 PDPR 70148344- 70148773- 70148834- Unc 0.272 0.268 −0.0059.18E−01 70148772 70148833 70154363 PDXDC2P 70010636- 70010714-70011907- Unc 0.250 0.246 −0.004 9.01E−01 70010713 70011906 70011979PDZD11 69509205- 69509372- 69509444- Inc 0.160 0.417 0.257 8.46E−3969509371 69509443 69509709 PEAK1 77544869- 77576225- 77576373- Exc 0.3710.201 −0.170 7.16E−08 77576224 77576372 77577299 PEAK1 77578847-77657505- 77657568- Unc 0.807 0.806 −0.001 9.36E−01 77657504 7765756777712347 PEX1 92136441- 92138643- 92138726- Exc 0.785 0.444 −0.3411.47E−05 92138642 92138725 92140257 PEX11A 90227180- 90229662- 90229778-Exc 0.719 0.316 −0.403 1.16E−07 90229661 90229777 90233807 PEX5 7354438-7354837- 7354948- Exc 0.442 0.279 −0.163 9.51E−06 7354836 73549477355207 PFDN1 139661119- 139680001- 139680168- Exc 0.784 0.458 −0.3261.30E−56 139680000 139680167 139682625 PFDN5 53689424- 53690214-53690336- Unc 0.167 0.175 0.008 9.25E−01 53690213 53690335 53691633PFDN5 53689424- 53690238- 53690336- Unc 0.173 0.180 0.007 9.26E−0153690237 53690335 53691633 PFDN6 33258022- 33258103- 33258228- Exc 0.9640.847 −0.117 1.39E−14 33258102 33258227 33258492 PFKM 48528822-48529074- 48529167- Exc 0.683 0.563 −0.120 1.32E−05 48529073 4852916648531503 PHC3 169840533- 169846128- 169846176- Inc 0.225 0.373 0.1486.06E−04 169846127 169846175 169846471 PHKG2 30764879- 30767503-30767594- Exc 0.976 0.799 −0.177 1.74E−07 30767502 30767593 30767687PHLDB1 118478415- 118484009- 118484166- Inc 0.095 0.239 0.143 5.84E−04118484008 118484165 118484530 PHLPP2 71715809- 71718379- 71718505- Unc0.866 0.867 0.001 9.68E−01 71718378 71718504 71724421 PI4KB 151280278-151282687- 151282732- Exc 0.296 0.168 −0.129 2.68E−07 151282686151282731 151288048 PI4KB 151288986- 151298648- 151298850- Exc 0.5090.314 −0.195 1.63E−06 151298647 151298849 151299746 PIGF 46808731-46815214- 46815319- Unc 0.142 0.139 −0.004 9.38E−01 46815213 4681531846819613 PIGG 521020- 524225- 524535- Exc 0.946 0.784 −0.162 3.14E−07524224 524534 527606 PIGN 59829563- 59830764- 59830890- Inc 0.622 0.9450.323 5.16E−07 59830763 59830889 59854076 PIGP 38441925- 38444445-38444611- Unc 0.161 0.163 0.001 9.58E−01 38444444 38444610 38444733 PIGQ630973- 632248- 632310- Unc 0.785 0.790 0.005 6.73E−01 632247 632309632882 PIGT 44044984- 44045157- 44045295- Exc 0.917 0.752 −0.1656.18E−17 44045156 44045294 44047934 PIGT 44044984- 44045157- 44045335-Exc 0.918 0.751 −0.167 3.18E−17 44045156 44045334 44047934 PIK3C2A17167490- 17169064- 17169176- Exc 0.982 0.871 −0.111 1.27E−08 1716906317169175 17170213 PIKFYVE 209138458- 209138742- 209138778- Exc 0.4990.309 −0.190 6.54E−04 209138741 209138777 209141435 PILRB 99950747-99950833- 99950894- Exc 0.952 0.688 −0.264 9.36E−10 99950832 9995089399952765 PIN1 9946079- 9947499- 9947552- Inc 0.025 0.131 0.107 4.07E−079947498 9947551 9949111 PINX1 10623427- 10677703- 10677780- Unc 0.7260.736 0.010 8.30E−01 10677702 10677779 10683661 PKIG 43160620- 43211226-43211373- Exc 0.569 0.417 −0.152 1.06E−06 43211225 43211372 43218437PLA2G12A 110638870- 110639839- 110639916- Exc 0.977 0.669 −0.3083.05E−28 110639838 110639915 110650757 PLA2G12A 110638870- 110639845-110639916- Exc 0.940 0.460 −0.480 4.91E−21 110639844 110639915 110650757PLA2R1 160832737- 160833196- 160833232- Exc 0.953 0.831 −0.122 2.11E−08160833195 160833231 160833794 PLAGL1 144290116- 144306272- 144306312-Exc 0.234 0.047 −0.187 2.90E−06 144306271 144306311 144329226 PLAGL1144285956- 144287295- 144287336- Exc 0.939 0.713 −0.225 1.52E−10144287294 144287335 144290043 PLAGL1 144285956- 144287295- 144287350-Exc 0.918 0.657 −0.261 1.80E−09 144287294 144287349 144290043 PLAGL1144285956- 144287295- 144287368- Exc 0.909 0.637 −0.272 3.25E−09144287294 144287367 144290043 PLBD2 113822071- 113822656- 113822752- Exc0.988 0.840 −0.148 1.86E−68 113822655 113822751 113823016 PLD3 40854632-40871460- 40871838- Unc 0.890 0.883 −0.007 5.77E−01 40871459 4087183740872325 PLD3 40854676- 40871625- 40871838- Unc 0.798 0.790 −0.0089.05E−01 40871624 40871837 40872290 PLSCR4 145941565- 145968344-145968425- Unc 0.700 0.691 −0.009 6.67E−01 145968343 145968424 145968746PMS2P3 75140437- 75141633- 75141746- Exc 0.932 0.700 −0.232 2.63E−0475141632 75141745 75141912 PNPLA8 108156019- 108161920- 108161966- Inc0.701 0.871 0.170 9.72E−05 108161919 108161965 108166472 PODNL114044807- 14046793- 14046858- Exc 0.645 0.491 −0.154 2.46E−06 1404679214046857 14047179 POLR3GL 145457605- 145457935- 145458004- Exc 0.9760.858 −0.118 1.04E−12 145457934 145458003 145459651 PPAP2A 54763978-54786788- 54786943- Exc 0.736 0.379 −0.356 4.31E−08 54786787 5478694254830399 PPFIBP1 27826761- 27827125- 27827155- Exc 0.858 0.757 −0.1003.19E−05 27827124 27827154 27829360 PPIL3 201746212- 201747065-201747159- Exc 0.868 0.767 −0.101 4.82E−04 201747064 201747158 201750420PPIL3 201746212- 201747065- 201747106- Exc 0.800 0.666 −0.134 8.74E−04201747064 201747105 201750420 PPIP5K2 102515890- 102518935- 102519109-Exc 0.381 0.132 −0.249 5.73E−16 102518934 102519108 102520372 PPM1M52280829- 52280990- 52281245- Exc 0.844 0.454 −0.390 1.59E−21 5228098952281244 52281697 PPP1R12A 80199549- 80199946- 80200114- Exc 0.738 0.616−0.122 1.02E−06 80199945 80200113 80201005 PPP1R12A 80199549- 80199946-80200078- Exc 0.642 0.515 −0.128 2.82E−05 80199945 80200077 80201005PPP1R18 30647167- 30652185- 30653824- Unc 0.868 0.877 0.009 7.54E−0130652184 30653823 30654890 PPP1R21 48725875- 48732703- 48732736- Exc0.918 0.799 −0.119 9.11E−04 48732702 48732735 48734407 PPP2R3C 35568591-35576510- 35576581- Exc 0.987 0.858 −0.129 4.10E−13 35576509 3557658035577344 PPP3CB 75198179- 75199630- 75199660- Inc 0.238 0.638 0.4016.54E−47 75199629 75199659 75204482 PPP3CC 22390532- 22396982- 22397012-Inc 0.100 0.299 0.199 1.62E−08 22396981 22397011 22398127 PPP4C30087797- 30092580- 30092632- Exc 0.957 0.851 −0.105 2.62E−16 3009257930092631 30093804 PPP4C 30087797- 30092521- 30092632- Exc 0.926 0.767−0.159 4.27E−15 30092520 30092631 30093804 PPP6R2 50874882- 50875417-50875498- Exc 0.490 0.339 −0.151 9.91E−07 50875416 50875497 50875934PPP6R3 68228296- 68272613- 68272740- Unc 0.419 0.422 0.003 9.79E−0168272612 68272739 68286968 PPP6R3 68228296- 68272613- 68272718- Unc0.248 0.240 −0.008 9.10E−01 68272612 68272717 68286968 PPRC1 103897796-103898376- 103898523- Exc 0.976 0.852 −0.124 8.23E−06 103898375103898522 103898635 PRDM5 121737730- 121737987- 121738080- Unc 0.8550.846 −0.010 8.96E−01 121737986 121738079 121739507 PREB 27354377-27354542- 27354700- Exc 0.971 0.867 −0.104 2.68E−05 27354541 2735469927354877 PREPL 44573530- 44586636- 44587178- Inc 0.142 0.262 0.1191.92E−04 44586635 44587177 44588518 PREPL 44573530- 44586636- 44586890-Inc 0.140 0.248 0.108 6.19E−04 44586635 44586889 44588518 PRKAG149399327- 49399526- 49399636- Exc 0.940 0.814 −0.126 2.16E−17 4939952549399635 49406844 PRKAG1 49399327- 49399526- 49399665- Exc 0.899 0.703−0.196 5.74E−17 49399525 49399664 49406844 PRKAG1 49397706- 49398290-49398417- Exc 0.977 0.763 −0.214 3.87E−53 49398289 49398416 49398746PRKAG1 49397074- 49397341- 49397379- Exc 0.985 0.741 −0.244 7.28E−7349397340 49397378 49397539 PRMT2 48069652- 48081712- 48081849- Exc 0.9810.783 −0.199 1.98E−09 48081711 48081848 48083294 PRPF39 45565432-45565627- 45565962- Inc 0.472 0.663 0.190 7.61E−04 45565626 4556596145566089 PRPF40B 50026664- 50026797- 50026908- Exc 0.888 0.566 −0.3221.00E−05 50026796 50026907 50027209 PRR16 119952888- 119954137-119954261- Exc 0.759 0.541 −0.218 2.87E−04 119954136 119954260 120021648PRR4 11126321- 11187381- 11187485- Exc 0.455 0.165 −0.290 5.30E−0911187380 11187484 11199618 PRRC2B 134349112- 134349841- 134351923- Unc0.770 0.776 0.006 8.86E−01 134349840 134351922 134353130 PRRX1170695543- 170699418- 170699490- Inc 0.538 0.681 0.143 8.34E−20170699417 170699489 170705188 PRUNE 150990381- 150991033- 150991146- Inc0.727 0.932 0.205 2.28E−05 150991032 150991145 150997086 PRUNE150990381- 150990943- 150991146- Inc 0.774 0.944 0.171 4.97E−05150990942 150991145 150997086 PRUNE 150999804- 151001262- 151001421- Unc0.759 0.768 0.009 9.56E−01 151001261 151001420 151006281 PSME4 54164678-54167093- 54167138- Exc 0.991 0.868 −0.123 6.57E−10 54167092 5416713754175557 PTAR1 72333601- 72338242- 72338547- Unc 0.873 0.866 −0.0069.96E−01 72338241 72338546 72347054 PTAR1 72356775- 72365697- 72365867-Unc 0.903 0.896 −0.008 9.79E−01 72365696 72365866 72374768 PTPN1387672278- 87674162- 87674219- Exc 0.423 0.293 −0.131 2.96E−05 8767416187674218 87679412 PTPN21 88962837- 88963547- 88963635- Exc 0.997 0.889−0.108 2.48E−10 88963546 88963634 88967126 PTPN23 47437708- 47446142-47446270- Exc 0.846 0.653 −0.193 1.09E−07 47446141 47446269 47446494PTPN4 120635119- 120639362- 120639407- Exc 0.945 0.633 −0.312 7.64E−08120639361 120639406 120639672 PTPRA 2903932- 2928628- 2928671- Exc 0.7330.548 −0.185 8.06E−12 2928627 2928670 2944917 PTPRG 62204658- 62216899-62216986- Unc 0.176 0.180 0.004 8.55E−01 62216898 62216985 62229480PTPRS 5218544- 5218798- 5218810- Unc 0.810 0.816 0.006 8.40E−01 52187975218809 5219320 PUF60 144900705- 144902836- 144902887- Unc 0.702 0.7060.004 8.39E−01 144902835 144902886 144903766 PUM2 20518407- 20526022-20526147- Unc 0.127 0.122 −0.005 9.57E−01 20526021 20526146 20527070 PVR45161179- 45162010- 45162169- Exc 0.822 0.704 −0.118 1.90E−08 4516200945162168 45164558 PVR 45161179- 45162010- 45162034- Exc 0.765 0.627−0.138 3.54E−08 45162009 45162033 45164558 PXDN 1687924- 1691404-1691476- Exc 0.818 0.560 −0.258  9.68E−121 1691403 1691475 1695699QTRTD1 113775712- 113775846- 113775954- Inc 0.328 0.715 0.387 9.51E−07113775845 113775953 113784083 R3HCC1L 99923155- 99946224- 99946321- Inc0.181 0.373 0.191 9.16E−04 99946223 99946320 99967857 R3HDM1 136362587-136374238- 136374328- Unc 0.194 0.189 −0.004 9.92E−01 136374237136374327 136379063 R3HDM4 900953- 901420- 901547- Exc 0.959 0.838−0.121 5.37E−07 901419 901546 901975 RAB11FIP2 119774622- 119793493-119793553- Exc 0.147 0.036 −0.110 2.48E−14 119793492 119793552 119798482RABEPK 127970001- 127982818- 127982980- Exc 0.824 0.631 −0.192 1.69E−06127982817 127982979 127990188 RAD1 34911918- 34913575- 34913684- Exc0.630 0.518 −0.112 4.26E−06 34913574 34913683 34914799 RAD51D 33433501-33434385- 33434467- Unc 0.181 0.182 0.001 9.34E−01 33434384 3343446633446129 RAF1 12645789- 12647700- 12647799- Unc 0.877 0.872 −0.0057.91E−01 12647699 12647798 12650264 RALGPS2 178858832- 178861365-178861443- Exc 0.299 0.071 −0.228 7.32E−14 178861364 178861442 178863053RALY 32661442- 32661625- 32661673- Inc 0.721 0.832 0.111 9.14E−1232661624 32661672 32663679 RAPH1 204326649- 204334962- 204335037- Unc0.185 0.191 0.005 6.97E−01 204334961 204335036 204354306 RBBP9 18474708-18476482- 18476525- Inc 0.845 0.961 0.116 3.55E−05 18476481 1847652418477712 RBCK1 400376- 401515- 401651- Exc 0.986 0.770 −0.216 8.18E−04401514 401650 402770 RBM10 47028898- 47030427- 47030658- Unc 0.773 0.764−0.009 9.45E−01 47030426 47030657 47032526 RBM27 145616996- 145631274-145631439- Unc 0.697 0.699 0.003 9.86E−01 145631273 145631438 145634505RBM4 66407595- 66410921- 66411612- Unc 0.792 0.800 0.009 7.93E−0166410920 66411611 66413497 RBM41 106332070- 106356627- 106356699- Inc0.206 0.467 0.262 1.16E−06 106356626 106356698 106358581 RBM5 50137485-50137965- 50138039- Unc 0.901 0.892 −0.009 7.37E−01 50137964 5013803850140515 RCC1 28856452- 28857035- 28857128- Unc 0.211 0.215 0.0049.95E−01 28857034 28857127 28858314 RCOR3 211477483- 211485697-211485830- Exc 0.148 0.048 −0.101 3.06E−05 211485696 211485829 211486061REPS1 139242262- 139247538- 139247619- Exc 0.328 0.187 −0.141 5.65E−04139247537 139247618 139251113 REV3L 111737676- 111793216- 111793344- Inc0.508 0.738 0.230 1.57E−08 111793215 111793343 111803952 RFC2 73657577-73660992- 73661094- Unc 0.898 0.892 −0.006 8.01E−01 73660991 7366109373663341 RFWD2 176104223- 176105624- 176105684- Inc 0.782 0.934 0.1527.36E−10 176105623 176105683 176118141 RGL1 183605637- 183666538-183666648- Unc 0.290 0.297 0.008 9.66E−01 183666537 183666647 183711260RGL2 33264893- 33266232- 33266429- Exc 0.872 0.647 −0.225 2.35E−0433266231 33266428 33266646 RGN 46944000- 46951077- 46951209- Exc 0.9240.580 −0.345 2.79E−05 46951076 46951208 46951459 RHBDD2 75508579-75510683- 75510805- Exc 0.388 0.279 −0.110 2.25E−04 75510682 7551080475511146 RHOBTB1 62631410- 62631801- 62632049- Exc 0.969 0.828 −0.1411.82E−05 62631800 62632048 62634711 RHOT1 30535329- 30538135- 30538258-Exc 0.379 0.258 −0.121 1.89E−04 30538134 30538257 30551634 RHOT130535329- 30536369- 30536465- Exc 0.205 0.065 −0.140 2.04E−07 3053636830536464 30551634 RHOT1 30535329- 30536369- 30536465- Exc 0.284 0.096−0.188 4.46E−05 30536368 30536464 30538134 RIF1 152276894- 152279464-152279557- Exc 0.995 0.814 −0.182 7.06E−08 152279463 152279556 152285297RIF1 152324661- 152324988- 152325066- Unc 0.593 0.600 0.006 8.92E−01152324987 152325065 152325154 RILP 1549914- 1550200- 1550284- Unc 0.6410.641 0.000 5.97E−01 1550199 1550283 1551128 RILPL2 123907705-123915055- 123915207- Unc 0.850 0.850 0.001 9.24E−01 123915054 123915206123920628 RIPK2 90770462- 90775057- 90775211- Exc 0.705 0.527 −0.1781.29E−03 90775056 90775210 90777568 RNASE4 21152918- 21161706- 21161810-Inc 0.172 0.283 0.112 1.19E−06 21161705 21161809 21167513 RNF14141353308- 141354369- 141354521- Unc 0.819 0.812 −0.007 8.30E−01141354368 141354520 141357867 RNF146 127601486- 127607195- 127607323-Exc 0.726 0.487 −0.239 2.13E−14 127607194 127607322 127607760 RNF17042716999- 42720559- 42720633- Exc 0.801 0.683 −0.118 6.72E−05 4272055842720632 42725146 RNF214 117153253- 117153462- 117153567- Exc 0.9860.818 −0.167 1.57E−08 117153461 117153566 117153830 RNF34 121838022-121840545- 121840611- Inc 0.031 0.154 0.123 9.16E−04 121840544 121840610121853961 RNF8 373448JO- 37348926- 37349131- Unc 0.898 0.893 −0.0059.04E−01 37348925 37349130 37358517 RNFT1 58035806- 58039901- 58039978-Exc 0.621 0.199 −0.422 2.53E−06 58039900 58039977 58040187 RNGTT89479594- 89511283- 89511352- Unc 0.908 0.900 −0.008 9.70E−01 8951128289511351 89554075 ROBO1 78695341- 78696779- 78696806- Exc 0.288 0.177−0.110 9.96E−04 78696778 78696805 78700881 RP11- 79412708- 79413764-79413857- Exc 0.430 0.173 −0.257 5.68E−04 1055B8.7 79413763 7941385679414061 RP11-14N7.2 148932921- 148933291- 148933369- Inc 0.244 0.4700.226 9.63E−19 148933290 148933368 148951244 RP11- 128214846- 128218018-128218088- Inc 0.564 0.975 0.411 1.21E−10 274B21.1 128218017 128218087128218943 RP11-33B1.1 120415679- 120418966- 120419059- Exc 0.958 0.767−0.190 1.45E−05 120418965 120419058 120420715 RP11- 72875284- 72885773-72885895- Exc 0.366 0.205 −0.162 2.32E−04 383H13.1 72885772 7288589472964773 RP11- 72875284- 72877644- 72877770- Exc 0.714 0.322 −0.3928.26E−31 383H13.1 72877643 72877769 72964773 RP11- 9808576- 9809164-9809294- Unc 0.108 0.115 0.007 9.25E−01 705C15.2 9809163 9809293 9809516RP11- 9808576- 9809164- 9809246- Unc 0.131 0.137 0.007 9.76E−01 705C15.29809163 9809245 9809516 RP11- 81565879- 81568515- 81568589- Exc 0.8860.668 −0.218 3.45E−15 773D16.1 81568514 81568588 81574368 RP11-81565879- 81568519- 81568720- Exc 0.504 0.147 −0.357 5.56E−10 773D16.181568518 81568719 81574368 RP1-178F15.4 153604717- 153605512- 153605634-Unc 0.221 0.228 0.008 5.93E−01 153605511 153605633 153606433 RP13-19212123- 19212958- 19213006- Exc 0.958 0.792 −0.166 4.30E−04 279N23.219212957 19213005 19215855 RPAIN 5326150- 5329556- 5329620- Exc 0.3690.208 −0.160 5.41E−05 5329555 5329619 5335861 RPAIN 5329403- 5329556-5329620- Exc 0.889 0.597 −0.293 2.20E−13 5329555 5329619 5335861 RPAIN5329403- 5331391- 5331532- Exc 0.808 0.420 −0.388 3.96E−11 53313905331531 5335861 RPAIN 5326150- 5329291- 5329403- Inc 0.773 0.916 0.1433.51E−08 5329290 5329402 5329555 RPAIN 5326150- 5329291- 5329620- Unc0.544 0.540 −0.004 9.53E−01 5329290 5329619 5335861 RPAIN 5329620-5331391- 5331532- Unc 0.686 0.678 −0.008 9.72E−01 5331390 53315315335861 RPL7L1 42847690- 42848599- 42848705- Exc 0.836 0.697 −0.1393.61E−12 42848598 42848704 42851188 RPL7L1 42847690- 42848599- 42848821-Exc 0.724 0.545 −0.179 7.34E−10 42848598 42848820 42851188 RPP1458292145- 58296017- 58296134- Exc 0.532 0.269 −0.263 4.78E−05 5829601658296133 58296233 RPP14 58292145- 58296036- 58296134- Exc 0.638 0.346−0.291 8.98E−07 58296035 58296133 58296233 RPP38 15139409- 15144217-15144336- Unc 0.547 0.545 −0.001 9.89E−01 15144216 15144335 15145303RPS24 79797063- 79799962- 79799984- Unc 0.887 0.887 0.000 8.72E−0179799961 79799983 79800372 RPS24 79797063- 79799959- 79799984- Unc 0.7880.787 −0.001 8.72E−01 79799958 79799983 79800372 RPS6KB2 67196095-67196453- 67196494- Exc 0.977 0.869 −0.108 3.73E−04 67196452 6719649367196590 RPS6KB2 67196095- 67196384- 67196494- Exc 0.965 0.797 −0.1673.88E−04 67196383 67196493 67196590 RPUSD1 836929- 837068- 837180- Unc0.884 0.885 0.001 9.88E−01 837067 837179 837353 RRBP1 17641174-17660644- 17660721- Inc 0.417 0.538 0.121 8.20E−09 17660643 1766072017662672 RRNAD1 156703313- 156703801- 156703845- Unc 0.517 0.523 0.0069.83E−01 156703800 156703844 156705516 RSU1 16824084- 16858972-16859084- Exc 0.911 0.802 −0.109 6.95E−22 16858971 16859083 16859313RTEL1 62325842- 62326094- 62326328- Exc 0.969 0.771 −0.197 2.00E−0462326093 62326327 62326418 RTEL1- 62325842- 62326094- 62326328- Exc0.969 0.771 −0.197 2.00E−04 TNFRSF6B 62326093 62326327 62326418 RTN245992812- 45996418- 45996637- Unc 0.584 0.577 −0.008 9.89E−01 4599641745996636 45997423 RUFY2 70154209- 70156537- 70156639- Exc 0.884 0.699−0.185 1.17E−07 70156536 70156638 70161376 RUNX1 36171760- 36206707-36206899- Unc 0.804 0.812 0.008 7.25E−01 36206706 36206898 36231770RWDD1 116892819- 116895221- 116895335- Inc 0.291 0.554 0.263 7.98E−40116895220 116895334 116901457 RWDD2B 30380445- 30380561- 30380629- Exc0.853 0.706 −0.147 1.60E−06 30380560 30380628 30380715 RWDD4 184572285-184572371- 184572481- Exc 0.976 0.815 −0.162 1.52E−17 184572370184572480 184577033 RWDD4 184572285- 184572371- 184572477- Exc 0.9630.742 −0.221 1.04E−15 184572370 184572476 184577033 SBF1 50895103-50895463- 50895541- Exc 0.669 0.512 −0.156 5.40E−05 50895462 5089554050897683 SCMH1 41617357- 41625397- 41625606- Exc 0.591 0.412 −0.1807.57E−04 41625396 41625605 41626546 SCRN3 175260546- 175262064-175262133- Unc 0.107 0.112 0.005 9.46E−01 175262063 175262132 175263002SDCCAG8 243456522- 243456701- 243456797- Inc 0.154 0.388 0.234 1.02E−09243456700 243456796 243468014 SEC13 10359779- 10360823- 10360857- Unc0.268 0.273 0.005 7.94E−01 10360822 10360856 10362192 SEC31A 83778918-83783687- 83783726- Unc 0.738 0.735 −0.003 8.76E−01 83783686 8378372583784470 SEC31A 83803094- 83819142- 83819216- Unc 0.873 0.868 −0.0048.31E−01 83819141 83819215 83821229 SEC31B 102249519- 102249765-102250080- Exc 0.783 0.464 −0.319 1.99E−05 102249764 102250079 102250462SECISBP2L 49309826- 49311615- 49311750- Exc 0.734 0.533 −0.201 1.87E−1049311614 49311749 49319561 SEMA4F 74884752- 74884980- 74885079- Exc0.302 0.016 −0.286 8.40E−07 74884979 74885078 74889858 SENP1 48459464-48460710- 48460749- Exc 0.959 0.742 −0.218 4.11E−09 48460709 4846074848465449 SENP6 76331342- 76332467- 76332575- Exc 0.227 0.126 −0.1011.01E−04 76332466 76332574 76333615 SENP6 76344528- 76350403- 76350421-Exc 0.717 0.594 −0.123 1.33E−04 76350402 76350420 76357446 SENP676344528- 76350400- 76350421- Exc 0.708 0.568 −0.140 1.63E−05 7635039976350420 76357446 SERAC1 158571622- 158576347- 158576384- Exc 0.7830.575 −0.208 7.72E−05 158576346 158576383 158579304 SETD2 47108609-47122406- 47122574- Unc 0.111 0.109 −0.002 9.11E−01 47122405 4712257347125209 SETD5 9476170- 9476274- 9476315- Exc 0.328 0.138 −0.1902.82E−11 9476273 9476314 9476507 SETX 135140373- 135144790- 135144877-Inc 0.316 0.466 0.150 3.99E−06 135144789 135144876 135145001 SEZ6L229883848- 29884026- 29884065- Unc 0.572 0.582 0.010 7.00E−01 2988402529884064 29884560 SFXN4 120920482- 120920567- 120920594- Exc 1.000 0.812−0.188 2.01E−06 120920566 120920593 120921851 SGSM2 2268636- 2270565-2270700- Unc 0.311 0.317 0.005 9.14E−01 2270564 2270699 2274555 SGSM340796818- 40797597- 40797680- Exc 0.784 0.494 −0.290 3.39E−19 4079759640797679 40798142 SH3D19 152065203- 152065372- 152065441- Inc 0.4770.620 0.143 5.12E−10 152065371 152065440 152069073 SHMT2 57624784-57625264- 57625344- Exc 0.892 0.754 −0.138 3.03E−40 57625263 5762534357625495 SIKE1 115321906- 115322731- 115322837- Unc 0.896 0.891 −0.0059.28E−01 115322730 115322836 115323069 SIPA1L1 71787899- 71867511-71867636- Exc 0.241 0.000 −0.241 8.40E−12 71867510 71867635 71979459SIPA1L1 71867636- 71880665- 71880732- Inc 0.609 0.986 0.377 2.94E−0871880664 71880731 71979459 SLAIN2 48385802- 48396593- 48396671- Unc0.726 0.717 −0.009 7.85E−01 48396592 48396670 48422141 SLC15A4129294019- 129294488- 129294599- Inc 0.869 0.982 0.113 5.60E−08129294487 129294598 129299319 SLC22A17 23816422- 23816723- 23816941- Exc0.855 0.684 −0.171 3.27E−04 23816722 23816940 23817369 SLC25A1741175130- 41188529- 41188681- Exc 0.969 0.772 −0.197 1.14E−05 4118852841188680 41195026 SLC25A17 41175130- 41190518- 41190585- Exc 0.966 0.769−0.197 4.59E−05 41190517 41190584 41195026 SLC25A32 104415553-104417004- 104417090- Exc 0.935 0.801 −0.134 4.51E−09 104417003104417089 104419861 SLC25A36 140682070- 140685842- 140685879- Exc 0.2730.073 −0.201 3.17E−11 140685841 140685878 140689768 SLC25A36 140682070-140685776- 140685879- Exc 0.326 0.096 −0.230 7.87E−13 140685775140685878 140689768 SLC30A6 32419053- 32422413- 32422462- Unc 0.7810.790 0.009 9.62E−01 32422412 32422461 32422775 SLC35A1 88182738-88187080- 88187258- Exc 0.954 0.760 −0.194 7.27E−08 88187079 8818725788210875 SLC35A3 100435719- 100440527- 100440626- Inc 0.377 0.613 0.2374.81E−04 100440526 100440625 100459092 SLC35D2 99083624- 99084280-99084363- Exc 0.977 0.841 −0.136 4.48E−07 99084279 99084362 99086372SLC37A3 140037150- 140045669- 140045771- Exc 0.790 0.548 −0.241 8.26E−05140045668 140045770 140048425 SLC38A2 46761124- 46764295- 46764411- Exc0.902 0.748 −0.154  4.38E−139 46764294 46764410 46764558 SLC38A661509931- 61510168- 61510222- Exc 0.865 0.653 −0.212 4.01E−06 6151016761510221 61512063 SLC38A6 61512886- 61517230- 61517355- Exc 0.988 0.717−0.271 2.20E−16 61517229 61517354 61518504 SLC38A6 61512886- 61514869-61515016- Inc 0.033 0.190 0.157 1.74E−04 61514868 61515015 61517229SLC38A9 54993821- 54998567- 54998723- Unc 0.125 0.116 −0.009 9.71E−0154998566 54998722 55007279 SLC39A9 69890920- 69908786- 69908984- Unc0.879 0.883 0.004 8.49E−01 69908785 69908983 69919957 SLC4A7 27446455-27450847- 27451022- Exc 0.804 0.378 −0.426 1.96E−29 27450846 2745102127453132 SLC5A6 27428962- 27429351- 27429403- Exc 0.938 0.763 −0.1745.73E−04 27429350 27429402 27429744 SLC7A6 68300625- 68307725- 68307808-Exc 0.429 0.224 −0.205 6.86E−07 68307724 68307807 68308593 SLC7A668300625- 68307721- 68307808- Exc 0.542 0.312 −0.230 6.22E−09 6830772068307807 68308593 SLC9B2 103947749- 103949904- 103950041- Exc 0.8750.553 −0.322 5.93E−13 103949903 103950040 103952856 SLFN11 33690846-33693966- 33694083- Unc 0.843 0.836 −0.006 9.73E−01 33693965 3369408233700492 SLFN11 33690846- 33693966- 33694063- Unc 0.843 0.836 −0.0079.49E−01 33693965 33694062 33700492 SLIT2 20547723- 20550111- 20550183-Exc 0.912 0.748 −0.163 2.81E−17 20550110 20550182 20550679 SLMAP57850444- 57857363- 57857426- Exc 0.606 0.339 −0.267 2.38E−05 5785736257857425 57875767 SLMAP 57882660- 57893611- 57893734- Unc 0.899 0.8990.000 9.81E−01 57893610 57893733 57894802 SLMO1 12421629- 12427040-12427111- Exc 0.984 0.854 −0.130 5.35E−06 12427039 12427110 12427219SLTM 59193487- 59204762- 59204810- Inc 0.825 0.928 0.104 9.23E−0559204761 59204809 59209133 SLTM 59191052- 59191668- 59192083- Unc 0.7300.731 0.001 9.55E−01 59191667 59192082 59193458 SLTM 59191052- 59191668-59192137- Unc 0.770 0.763 −0.007 7.30E−01 59191667 59192136 59193458SMAD5 135468652- 135483521- 135483596- Exc 0.787 0.590 −0.197 6.32E−07135483520 135483595 135489280 SMARCA1 128626071- 128627017- 128627053-Inc 0.618 0.870 0.253 3.54E−33 128627016 128627052 128630726 SMARCD150480662- 50481146- 50481269- Exc 0.800 0.548 −0.252 3.33E−18 5048114550481268 50482303 SMC5 72879362- 72882839- 72882892- Exc 0.979 0.854−0.125 5.98E−08 72882838 72882891 72892225 SMEK2 55795500- 55800755-55800914- Exc 0.955 0.819 −0.136 1.39E−13 55800754 55800913 55804450SMEK2 55804493- 55805383- 55805479- Unc 0.450 0.445 −0.005 9.40E−0155805382 55805478 55806814 SMG7 183441785- 183471388- 183471527- Unc0.206 0.200 −0.006 9.36E−01 183471387 183471526 183481971 SMPDL3A123110604- 123116822- 123117036- Exc 0.855 0.702 −0.152 1.92E−04123116821 123117035 123117968 SMURF2 62594609- 62602720- 62602759- Exc0.892 0.742 −0.150 9.59E−05 62602719 62602758 62657946 SMURF2 62589692-62590109- 62590223- Unc 0.111 0.111 −0.001 8.17E−01 62590108 6259022262594499 SNAPC5 66786891- 66787668- 66787758- Exc 0.779 0.646 −0.1331.46E−04 66787667 66787757 66789979 SNED1 241992744- 242002208-242002322- Exc 0.880 0.660 −0.220 9.72E−05 242002207 242002321 242003003SNHG14 25357042- 25360446- 25360804- Exc 0.979 0.860 −0.119 1.90E−0525360445 25360803 25362556 SNHG14 25328675- 25330337- 25330470- Unc0.851 0.852 0.001 9.66E−01 25330336 25330469 25332613 SNHG15 45023646-45023956- 45024026- Exc 0.960 0.832 −0.127 1.03E−05 45023955 4502402545025619 SNRNP70 49604729- 49605371- 49606845- Inc 0.210 0.325 0.1145.34E−16 49605370 49606844 49607890 SNRNP70 49604729- 49605371-49605431- Inc 0.201 0.302 0.102 2.96E−13 49605370 49605430 49607890SNRNP70 49604729- 49605371- 49605443- Inc 0.199 0.299 0.100 6.96E−1349605370 49605442 49607890 SNRPA1 101826007- 101826419- 101826499- Exc0.708 0.499 −0.209 1.53E−11 101826418 101826498 101827112 SNRPG70515325- 70516482- 70516505- Exc 0.856 0.696 −0.160 1.18E−28 7051648170516504 70520749 SNX14 86246643- 86248556- 86248583- Exc 0.829 0.668−0.160 6.31E−15 86248555 86248582 86251702 SNX21 44463756- 44468961-44469098- Exc 0.314 0.167 −0.148 2.05E−04 44468960 44469097 44469277SNX21 44463756- 44469087- 44469098- Exc 0.423 0.263 −0.160 6.59E−0544469086 44469097 44469277 SPATA20 48626548- 48626647- 48626849- Exc0.979 0.856 −0.123 9.61E−18 48626646 48626848 48627345 SPATA20 48624647-48625026- 48625129- Exc 0.948 0.815 −0.133 1.65E−08 48625025 4862512848625643 SPATA20 48624647- 48625081- 48625129- Exc 0.943 0.792 −0.1511.04E−08 48625080 48625128 48625643 SPATA20 48624647- 48625026-48625316- Exc 0.790 0.531 −0.259 8.43E−05 48625025 48625315 48625643SPATA20 48624647- 48625081- 48625316- Exc 0.647 0.347 −0.300 9.22E−0448625080 48625315 48625643 SPATA7 88857800- 88859737- 88859833- Inc0.670 0.925 0.255 4.37E−05 88859736 88859832 88862499 SPDL1 169015580-169017757- 169017834- Inc 0.107 0.355 0.248 7.98E−13 169017756 169017833169018051 SPDL1 169015580- 169017760- 169017834- Inc 0.104 0.345 0.2411.54E−12 169017759 169017833 169018051 SPEN 16199632- 16202697-16203174- Unc 0.859 0.861 0.002 9.99E−01 16202696 16203173 16235815SPIDR 48206620- 48320423- 48320524- Unc 0.885 0.878 −0.007 9.47E−0148320422 48320523 48352884 SPPL2A 51017521- 51018270- 51018324- Inc0.176 0.554 0.378 4.89E−81 51018269 51018323 51018517 SPTAN1 131353905-131355262- 131355322- Exc 0.289 0.040 −0.249 1.83E−69 131355261131355321 131356453 SRSF2 74731241- 74731854- 74731958- Unc 0.112 0.1130.001 9.79E−01 74731853 74731957 74732235 ST6GALNAC6 130658612-130660235- 130660290- Inc 0.529 0.659 0.130 3.79E−04 130660234 130660289130661781 ST7 116849992- 116859138- 116859231- Exc 0.994 0.857 −0.1373.24E−05 116859137 116859230 116869815 ST7 116849992- 116861977-116862117- Exc 0.989 0.771 −0.218 7.60E−05 116861976 116862116 116869815STAG1 136261038- 136287607- 136287704- Unc 0.878 0.885 0.007 7.91E−01136287606 136287703 136323150 STAG2 123094717- 123155217- 123155282- Unc0.278 0.279 0.002 9.96E−01 123155216 123155281 123156380 STARD337814776- 37814962- 37815074- Unc 0.862 0.871 0.009 8.06E−01 3781496137815073 37815303 STARD3NL 38218023- 38218692- 38218748- Inc 0.087 0.1950.108 1.74E−04 38218691 38218747 38247047 STARD4 110836815- 110837660-110837787- Unc 0.769 0.760 −0.008 9.68E−01 110837659 110837786 110842027STARD5 81614882- 81615240- 81615290- Exc 0.949 0.780 −0.169 1.97E−0481615239 81615289 81616142 STAT6 57501098- 57501442- 57501527- Exc 0.8560.732 −0.124 1.48E−08 57501441 57501526 57501945 STK16 220111599-220111835- 220111969- Exc 0.919 0.703 −0.216 4.52E−20 220111834220111968 220112136 STK19 31946776- 31947191- 31947331- Exc 0.943 0.773−0.171 2.51E−11 31947190 31947330 31948227 STK38L 27455122- 27461272-27461395- Unc 0.907 0.898 −0.008 9.94E−01 27461271 27461394 27462046STK40 36826942- 36833453- 36833686- Inc 0.242 0.551 0.309 7.98E−0836833452 36833685 36851323 STK40 36826942- 36833449- 36833686- Inc 0.1370.358 0.221 1.21E−04 36833448 36833685 36851323 STOML1 74281144-74281371- 74281599- Unc 0.817 0.818 0.001 8.95E−01 74281370 7428159874282691 STOML1 74281144- 74281449- 74281599- Unc 0.901 0.898 −0.0048.91E−01 74281448 74281598 74282691 STRA13 79977258- 79977386- 79977571-Exc 0.368 0.142 −0.226 1.53E−08 79977385 79977570 79977733 STRA1379977258- 79977517- 79977571- Exc 0.510 0.249 −0.261 8.77E−11 7997751679977570 79977733 STRADA 61784100- 61784607- 61784779- Exc 0.961 0.833−0.129 8.80E−06 61784606 61784778 61787850 STRN3 31382864- 31388172-31388313- Inc 0.077 0.187 0.110 1.98E−05 31388171 31388312 31404368STX16 57243184- 57244347- 57244510- Exc 0.822 0.495 −0.327 9.78E−3957244346 57244509 57245567 STX16 57243184- 57244358- 57244510- Exc 0.7150.335 −0.380 1.01E−32 57244357 57244509 57245567 STX16- 57243184-57244347- 57244510- Exc 0.822 0.495 −0.327 9.78E−39 NPEPL1 5724434657244509 57245567 STX3 59562956- 59564756- 59564870- Exc 0.868 0.629−0.239 1.40E−09 59564755 59564869 59568327 STXBP3 109319046- 109321908-109322033- Exc 0.990 0.862 −0.128 6.63E−12 109321907 109322032 109325043STXBP5 147660375- 147660473- 147660521- Unc 0.829 0.827 −0.002 9.55E−01147660472 147660520 147674458 STYXL1 75634723- 75643060- 75643206- Exc0.749 0.572 −0.177 1.03E−06 75643059 75643205 75651168 SUCO 172520767-172522400- 172522511- Inc 0.605 0.967 0.362 2.47E−27 172522399 172522510172525008 SUGP2 19101959- 19104457- 19104550- Inc 0.791 0.902 0.1111.27E−03 19104456 19104549 19105174 SUGP2 19101959- 19104447- 19104550-Inc 0.802 0.908 0.106 9.46E−04 19104446 19104549 19105174 SUGT153233385- 53235610- 53235706- Exc 0.411 0.285 −0.126 1.95E−07 5323560953235705 53236783 SULF1 70379186- 70408000- 70408162- Exc 0.652 0.446−0.206 1.38E−87 70407999 70408161 70414108 SULF1 70541915- 70550737-70550880- Exc 0.911 0.702 −0.209 0.00E+00 70550736 70550879 70550969SUN2 39148671- 39150647- 39150712- Exc 0.353 0.221 −0.132 1.12E−0339150646 39150711 39151767 SUOX 56391124- 56391399- 56391508- Unc 0.6310.626 −0.005 9.30E−01 56391398 56391507 56395995 SUPT20H 37622074-37622701- 37622737- Exc 0.766 0.609 −0.157 4.61E−05 37622700 3762273637625624 SUPT20H 37583947- 37584689- 37584793- Inc 0.420 0.779 0.3593.13E−21 37584688 37584792 37586328 SYNE1 152615263- 152621776-152621917- Unc 0.784 0.778 −0.006 6.13E−01 152621775 152621916 152623003SYNJ2BP 70842489- 70855187- 70855324- Unc 0.876 0.869 −0.007 8.71E−0170855186 70855323 70883616 SYNRG 35879175- 35880282- 35880318- Inc 0.4600.836 0.377 2.57E−20 35880281 35880317 35880640 TAF1 70678217- 70679000-70679102- Exc 0.253 0.082 −0.171 1.03E−07 70678999 70679101 70679401TAF2 120756634- 120757121- 120757277- Inc 0.069 0.176 0.107 1.20E−04120757120 120757276 120758944 TAMM41 11871339- 11874477- 11874626- Unc0.124 0.122 −0.002 9.01E−01 11874476 11874625 11880695 TANGO2 20043537-20049053- 20049230- Exc 0.985 0.855 −0.130 2.86E−05 20049052 2004922920050860 TANGO2 20040108- 20040883- 20041075- Exc 0.456 0.293 −0.1634.78E−05 20040882 20041074 20043465 TANGO2 20040108- 20040960- 20041075-Exc 0.585 0.412 −0.173 2.36E−06 20040959 20041074 20043465 TARBP253898600- 53898919- 53899047- Exc 0.810 0.650 −0.160 1.16E−04 5389891853899046 53899432 TAS2R14 11126321- 11187381- 11187485- Exc 0.455 0.165−0.290 5.30E−09 11187380 11187484 11199618 TAZ 153647963- 153648044-153648086- Exc 0.874 0.620 −0.254 1.12E−05 153648043 153648085 153648370TBC1D14 7008454- 7011604- 7011676- Exc 0.857 0.729 −0.128 2.05E−067011603 7011675 7012379 TBC1D17 50386150- 50386230- 50386334- Exc 0.9940.892 −0.102 3.08E−11 50386229 50386333 50386907 TBC1D25 48399831-48403257- 48403412- Exc 0.691 0.459 −0.232 3.35E−04 48403256 4840341148417284 TBC1D32 121482203- 121491551- 121491674- Unc 0.890 0.885 −0.0069.13E−01 121491550 121491673 121526220 TBC1D5 17550098- 17665341-17665406- Exc 0.806 0.498 −0.308 3.67E−13 17665340 17665405 17783972TBCE 235543465- 235564818- 235564903- Unc 0.805 0.814 0.009 9.68E−01235564817 235564902 235577747 TBCEL 120918377- 120924260- 120924442- Unc0.813 0.805 −0.008 7.85E−01 120924259 120924441 120925760 TBCK107114928- 107115875- 107115912- Exc 0.936 0.549 −0.387 6.40E−56107115874 107115911 107133906 TBCK 107173165- 107176104- 107176205- Inc0.047 0.406 0.360 4.86E−30 107176103 107176204 107181593 TBPL1134273869- 134274323- 134274564- Inc 0.633 0.887 0.253 9.06E−04134274322 134274563 134301219 TBX15 119466227- 119467269- 119467441- Exc0.972 0.815 −0.157 3.14E−06 119467268 119467440 119469132 TCERG1145888809- 145889630- 145889724- Exc 0.227 0.120 −0.107 9.87E−04145889629 145889723 145890003 TCF20 42557365- 42564615- 42564743- Unc0.243 0.233 −0.010 9.77E−01 42564614 42564742 42565852 TCF7L2 114917829-114918426- 114918477- Unc 0.770 0.780 0.010 7.78E−01 114918425 114918476114920377 TCF7L2 114917829- 114919679- 114919752- Unc 0.516 0.525 0.0099.75E−01 114919678 114919751 114920377 TCF7L2 114917829- 114919679-114919752- Unc 0.338 0.334 −0.004 6.21E−01 114919678 114919751 114925313TEAD2 49858677- 49859216- 49859228- Exc 0.413 0.183 −0.230 6.40E−1149859215 49859227 49860508 TENM2 167182198- 167302991- 167303201- Unc0.873 0.878 0.005 6.28E−01 167302990 167303200 167379592 TENM2167631627- 167638739- 167638760- Unc 0.143 0.138 −0.005 8.43E−01167638738 167638759 167642044 TEP1 20849561- 20849712- 20849846- Exc0.602 0.343 −0.258 1.09E−05 20849711 20849845 20850071 TEP1 20839792-20840892- 20841017- Exc 0.758 0.466 −0.293 1.63E−09 20840891 2084101620841169 TET2 106068137- 106111517- 106111663- Unc 0.732 0.724 −0.0089.36E−01 106111516 106111662 106155053 TFB2M 246714605- 246719875-246720024- Unc 0.873 0.864 −0.009 9.05E−01 246719874 246720023 246727647TFDP1 114277602- 114285938- 114286060- Exc 0.923 0.820 −0.103 5.57E−17114285937 114286059 114287434 TFDP1 114277602- 114285938- 114286221- Exc0.853 0.685 −0.168 1.24E−15 114285937 114286220 114287434 TFDP2141724387- 141772957- 141772992- Exc 0.260 0.116 −0.144 1.48E−04141772956 141772991 141811902 TFDP2 141697525- 141712380- 141712428- Unc0.864 0.869 0.005 9.77E−01 141712379 141712427 141724282 TFDP2141697525- 141713862- 141713984- Unc 0.857 0.847 −0.010 6.43E−01141713861 141713983 141724282 TFPI 188368498- 188394091- 188394213- Exc0.214 0.058 −0.156 1.45E−10 188394090 188394212 188418926 TGFBR230648470- 30664691- 30664766- Inc 0.247 0.361 0.114 1.28E−15 3066469030664765 30686238 TGIF1 3450069- 3450323- 3450504- Unc 0.727 0.736 0.0096.27E−01 3450322 3450503 3456351 THADA 43625279- 43657352- 43657442- Unc0.858 0.859 0.000 9.41E−01 43657351 43657441 43712372 THAP6 76442190-76446946- 76447072- Exc 0.949 0.794 −0.155 2.70E−04 76446945 7644707176452169 THAP9-AS1 83816928- 83819142- 83819216- Inc 0.865 0.971 0.1062.38E−05 83819141 83819215 83821229 THBS3 155173097- 155173304-155173331- Exc 0.984 0.861 −0.123 1.84E−05 155173303 155173330 155174850THBS3 155169905- 155170242- 155170402- Exc 0.930 0.744 −0.186 2.81E−24155170241 155170401 155170687 THOC2 122757135- 122757495- 122757561- Exc0.188 0.077 −0.111 1.23E−03 122757494 122757560 122757637 THTPA24025553- 24025952- 24026249- Unc 0.291 0.297 0.005 9.10E−01 2402595124026248 24027903 THTPA 24025553- 24025952- 24026244- Unc 0.270 0.263−0.008 9.94E−01 24025951 24026243 24027903 TIA1 70454955- 70455476-70455595- Inc 0.210 0.532 0.322 1.88E−12 70455475 70455594 70456190 TIA170451762- 70452460- 70452526- Inc 0.123 0.374 0.251 2.51E−14 7045245970452525 70454866 TIAL1 121339523- 121339983- 121340359- Inc 0.068 0.2780.210 5.41E−34 121339982 121340358 121341433 TIAL1 121339523- 121339983-121340051- Inc 0.072 0.178 0.106 8.55E−12 121339982 121340050 121341433TIMM17B 48752385- 48752635- 48752785- Inc 0.105 0.216 0.111 1.53E−0548752634 48752784 48754041 TIMM21 71816345- 71822380- 71822443- Exc1.000 0.836 −0.164 2.93E−14 71822379 71822442 71822540 TJAP1 43445971-43446397- 43446457- Unc 0.181 0.180 −0.001 9.49E−01 43446396 4344645643465618 TJP1 30011343- 30011981- 30012221- Unc 0.317 0.310 −0.0079.42E−01 30011980 30012220 30012561 TLK2 60600539- 60601597- 60601693-Unc 0.413 0.423 0.010 9.00E−01 60601596 60601692 60613530 TM7SF327128592- 27129193- 27129291- Inc 0.836 0.966 0.129 2.07E−09 2712919227129290 27133498 TMCO4 20067435- 20072025- 20072145- Exc 0.711 0.348−0.364 6.18E−05 20072024 20072144 20072948 TMEM11 21102154- 21114249-21114541- Exc 0.327 0.206 −0.121 1.46E−05 21114248 21114540 21117403TMEM119 108986174- 108987940- 108988322- Unc 0.306 0.302 −0.004 6.73E−01108987939 108988321 108991745 TMEM120A 75616747- 75616856- 75616921- Exc0.963 0.574 −0.389 1.44E−31 75616855 75616920 75617035 TMEM126B85339733- 85342189- 85342361- Inc 0.622 0.779 0.157 7.27E−10 8534218885342360 85342730 TMEM126B 85339733- 85340176- 85340307- Inc 0.053 0.1980.145 1.01E−05 85340175 85340306 85342730 TMEM161B 87524346- 87536630-87536734- Unc 0.824 0.818 −0.006 8.70E−01 87536629 87536733 87564537TMEM175 926329- 941497- 941943- Unc 0.531 0.525 −0.007 9.38E−01 941496941942 944208 TMEM18 675631- 675758- 676239- Inc 0.104 0.246 0.1431.52E−06 675757 676238 677288 TMEM194A 57458523- 57463017- 57463090- Exc0.855 0.568 −0.287 1.77E−04 57463016 57463089 57464602 TMEM230 5090092-5092146- 5092252- Unc 0.508 0.505 −0.003 9.86E−01 5092145 50922515093388 TMEM234 32682953- 32683038- 32683179- Inc 0.094 0.210 0.1169.14E−05 32683037 32683178 32686731 TMEM260 57085482- 57088249-57088421- Exc 0.884 0.727 −0.157 9.42E−04 57088248 57088420 57092099TMEM260 57082746- 57083901- 57084016- Exc 0.964 0.804 −0.161 1.21E−0557083900 57084015 57085311 TMEM39B 32541424- 32542765- 32542920- Exc0.772 0.276 −0.496 2.72E−08 32542764 32542919 32557275 TMEM62 43461876-43470805- 43470910- Exc 0.978 0.786 −0.192 7.18E−07 43470804 4347090943473378 TMOD2 52073372- 52074918- 52075026- Exc 0.993 0.862 −0.1311.39E−04 52074917 52075025 52090393 TMUB2 42264478- 42265044- 42265112-Exc 0.898 0.675 −0.223 4.21E−06 42265043 42265111 42265274 TMUB242266668- 42266779- 42266957- Unc 0.846 0.849 0.004 9.41E−01 4226677842266956 42267868 TMUB2 42266668- 42266792- 42266957- Unc 0.844 0.8480.003 9.51E−01 42266791 42266956 42267868 TMX3 66367723- 66368982-66369028- Exc 0.967 0.821 −0.146 5.98E−29 66368981 66369027 66377257TOM1 35713955- 35717952- 35718013- Exc 0.931 0.817 −0.114 2.97E−1035717951 35718012 35719020 TOR1AIP2 179821947- 179834571- 179834990- Unc0.810 0.814 0.005 9.93E−01 179834570 179834989 179846373 TOR3A179052189- 179054763- 179055029- Unc 0.886 0.890 0.004 9.77E−01179054762 179055028 179057045 TP53BP2 224002056- 224005908- 224006040-Unc 0.108 0.118 0.010 8.29E−01 224005907 224006039 224008921 TP53INP195942957- 95944298- 95944336- Exc 0.573 0.361 −0.212 1.18E−09 9594429795944335 95952087 TP53TG1 86971001- 86974359- 86974550- Exc 0.583 0.415−0.168 1.27E−04 86974358 86974549 86974620 TPD52L1 125569530- 125578244-125578305- Inc 0.338 0.440 0.102 1.32E−04 125578243 125578304 125583979TPD52L2 62505170- 62507169- 62507229- Exc 0.868 0.741 −0.126 3.05E−3262507168 62507228 62514071 TPRA1 127294349- 127294592- 127294653- Exc0.909 0.621 −0.288 4.41E−39 127294591 127294652 127294782 TPT1-AS145957371- 45957895- 45957974- Inc 0.259 0.514 0.255 6.01E−04 4595789445957973 45963869 TPT1-AS1 45963956- 45964893- 45965038- Inc 0.792 0.9410.149 2.04E−04 45964892 45965037 45965166 TPT1-AS1 45963956- 45964849-45965038- Inc 0.835 0.950 0.116 4.16E−04 45964848 45965037 45965166TRA2A 23561460- 23561740- 23562052- Unc 0.101 0.104 0.003 9.31E−0123561739 23562051 23571407 TRAPPC12 3469467- 3481463- 3481567- Exc 0.9730.858 −0.115 6.99E−05 3481462 3481566 3482616 TREX2 152719967-152720335- 152720512- Exc 0.465 0.347 −0.119 9.05E−04 152720334152720511 152720999 TRIM16 15546131- 15554405- 15555261- Inc 0.791 0.9550.164 1.23E−05 15554404 15555260 15580489 TRIM37 57076821- 57078959-57079103- Unc 0.841 0.835 −0.005 9.69E−01 57078958 57079102 57089688TRIM65 73887429- 73887894- 73887960- Inc 0.430 0.645 0.214 1.65E−0473887893 73887959 73888091 TRIO 14502767- 14504502- 14504703- Exc 0.9870.870 −0.117 1.47E−17 14504501 14504702 14507230 TRIP10 6745006-6746040- 6746208- Exc 0.353 0.207 −0.146 9.68E−08 6746039 67462076746462 TRIP12 230724291- 230725122- 230725248- Inc 0.564 0.760 0.1951.78E−18 230725121 230725247 230744697 TRMU 46751486- 46751887-46751970- Unc 0.826 0.836 0.010 9.49E−01 46751886 46751969 46752738TROVE2 193038765- 193039684- 193039750- Inc 0.039 0.308 0.269 3.64E−15193039683 193039749 193044949 TROVE2 193028907- 193029004- 193029353-Unc 0.156 0.148 −0.008 9.76E−01 193029003 193029352 193038163 TRPC1142510001- 142511666- 142511810- Exc 0.886 0.735 −0.151 1.77E−04142511665 142511809 142521010 TRPM4 49661517- 49669298- 49669473- Exc1.000 0.794 −0.206 4.10E−04 49669297 49669472 49671516 TRPT1 63991440-63991572- 63991683- Exc 0.955 0.795 −0.160 2.78E−12 63991571 6399168263991756 TRPT1 63991440- 63991572- 63991635- Exc 0.927 0.704 −0.2232.99E−11 63991571 63991634 63991756 TSEN15 184023998- 184041291-184041433- Exc 0.766 0.618 −0.149 5.24E−09 184041290 184041432 184041960TSEN15 184023998- 184041291- 184041329- Exc 0.636 0.451 −0.186 4.32E−08184041290 184041328 184041960 TSEN15 184023998- 184039750- 184039867-Inc 0.032 0.171 0.139 1.01E−12 184039749 184039866 184041290 TSPAN599403327- 99407889- 99408036- Unc 0.851 0.857 0.006 8.52E−01 9940788899408035 99428828 TSR1 2239025- 2239331- 2239435- Exc 0.967 0.825 −0.1422.43E−09 2239330 2239434 2239624 TSTD3 99973986- 99979239- 99979413- Exc0.692 0.476 −0.216 3.86E−05 99979238 99979412 99979507 TUBG2 40812726-40814991- 40815071- Exc 0.929 0.811 −0.119 1.94E−04 40814990 4081507040815394 TULP3 3043728- 3046797- 3046896- Exc 0.947 0.671 −0.2761.33E−24 3046796 3046895 3047279 TULP3 3018747- 3029929- 3030089- Unc0.766 0.765 −0.001 9.89E−01 3029928 3030088 3031427 TXNDC11 11792182-11794308- 11794421- Exc 0.897 0.758 −0.139 3.52E−06 11794307 1179442011815432 TXNDC11 11815527- 11824501- 11824631- Exc 0.896 0.728 −0.1688.33E−07 11824500 11824630 11827837 TXNL4A 77737702- 77746602- 77746751-Inc 0.109 0.212 0.102 2.71E−13 77746601 77746750 77748239 U2AF144520630- 44521476- 44521543- Unc 0.143 0.143 0.001 9.72E−01 4452147544521542 44524424 U2AF1L4 36235323- 36235527- 36235640- Exc 0.519 0.093−0.426 1.77E−15 36235526 36235639 36236025 U2AF1L4 36235323- 36235527-36235594- Exc 0.538 0.066 −0.471 1.56E−18 36235526 36235593 36236025UACA 70968931- 70969447- 70969480- Exc 0.936 0.753 −0.183 3.76E−1770969446 70969479 70970437 UBA7 49849977- 49850081- 49850172- Exc 0.9710.826 −0.145 6.17E−08 49850080 49850171 49850494 UBE2A 118709364-118715470- 118715560- Exc 0.886 0.683 −0.203 1.92E−45 118715469118715559 118716550 UBE2D1 60121162- 60121255- 60121287- Exc 0.992 0.865−0.126 1.19E−14 60121254 60121286 60123368 UBN2 138921844- 138936702-138936804- Exc 0.910 0.653 −0.257 4.56E−04 138936701 138936803 138943233UBP1 33444397- 33450182- 33450290- Inc 0.356 0.568 0.212 2.16E−1633450181 33450289 33450727 UBQLN1 86280061- 86281265- 86281349- Exc0.813 0.711 −0.102 1.70E−10 86281264 86281348 86284099 UBQLN1 86280061-86281265- 86281310- Exc 0.687 0.557 −0.130 2.08E−08 86281264 8628130986284099 UCHL5 192993077- 192997005- 192997086- Unc 0.119 0.122 0.0039.32E−01 192997004 192997085 192997214 UFD1L 19459332- 19462993-19463126- Exc 0.821 0.658 −0.164 4.55E−06 19462992 19463125 19466605UNC5B 73048490- 73048715- 73048748- Exc 0.964 0.839 −0.125 2.93E−0873048714 73048747 73050671 UPF3A 115048419- 115051734- 115051876- Unc0.532 0.530 −0.002 9.49E−01 115051733 115051875 115051993 UPF3A115048419- 115051777- 115051876- Unc 0.630 0.622 −0.008 9.23E−01115051776 115051875 115051993 UPP1 48134425- 48141421- 48141468- Unc0.195 0.185 −0.010 7.14E−01 48141420 48141467 48146469 URGCP 43927085-43927389- 43927416- Exc 0.925 0.790 −0.136 8.53E−05 43927388 4392741543946160 URGCP 43927085- 43927389- 43927411- Exc 0.900 0.708 −0.1912.51E−05 43927388 43927410 43946160 USMG5 105152224- 105153956-105154152- Exc 0.530 0.311 −0.220 1.87E−06 105153955 105154151 105155502USP24 55557800- 55558494- 55558590- Exc 0.990 0.881 −0.108 2.57E−0855558493 55558589 55559609 USP25 17177578- 17181128- 17181205- Exc 0.9830.835 −0.148 1.91E−13 17181127 17181204 17183455 USP3 63824907-63826002- 63826118- Unc 0.101 0.094 −0.006 8.98E−01 63826001 6382611763829223 USP33 78207434- 78211106- 78211285- Inc 0.414 0.558 0.1449.65E−05 78211105 78211284 78225327 USP53 120134029- 120135225-120135378- Exc 0.631 0.332 −0.300 1.17E−16 120135224 120135377 120138704USP8 50774263- 50776472- 50776559- Inc 0.466 0.594 0.127 1.87E−0650776471 50776558 50781997 VAMP7 155119276- 155125286- 155125344- Exc0.957 0.830 −0.127 4.67E−13 155125285 155125343 155127775 VCAN 82808216-82815168- 82818129- Exc 0.685 0.357 −0.328 7.07E−14 82815167 8281812882841355 VDR 48272899- 48276477- 48276558- Unc 0.878 0.876 −0.0027.96E−01 48276476 48276557 48298737 VEGFA 43746656- 43748469- 43748592-Unc 0.115 0.123 0.009 8.73E−01 43748468 43748591 43749692 VEGFA43746656- 43748469- 43748523- Unc 0.140 0.145 0.005 9.83E−01 4374846843748522 43749692 VEZT 95645848- 95650326- 95650399- Inc 0.510 0.6680.157 2.20E−07 95650325 95650398 95650925 VIPAS39 77920446- 77923438-77923757- Unc 0.130 0.125 −0.005 9.28E−01 77923437 77923756 77923837VPS13D 12395885- 12398288- 12398363- Unc 0.126 0.117 −0.009 9.68E−0112398287 12398362 12401836 VPS29 110934009- 110937340- 110937352- Inc0.356 0.468 0.113 3.40E−06 110937339 110937351 110939853 WARS 100828259-100841620- 100841744- Unc 0.507 0.515 0.007 9.35E−01 100841619 100841743100842596 WARS 100835596- 100840473- 100840582- Unc 0.249 0.240 −0.0095.31E−01 100840472 100840581 100841619 WBP1 74685799- 74686605-74686690- Exc 0.239 0.112 −0.127 6.92E−05 74686604 74686689 74686769WDFY2 52234800- 52249306- 52249380- Exc 0.833 0.606 −0.226 2.21E−0652249305 52249379 52277731 WDR27 170062521- 170063659- 170063746- Unc0.353 0.358 0.005 9.09E−01 170063658 170063745 170064261 WHSC1 1936990-1941381- 1941506- Unc 0.739 0.741 0.001 9.07E−01 1941380 1941505 1952798WNK1 971437- 980431- 980515- Unc 0.768 0.770 0.002 9.77E−01 980430980514 987380 XIAP 122993756- 123019481- 123020390- Unc 0.893 0.8960.003 9.33E−01 123019480 123020389 123022468 XPNPEP3 41265120- 41266052-41266144- Unc 0.230 0.223 −0.008 9.33E−01 41266051 41266143 41277773YEATS2 183476754- 183479295- 183479403- Exc 1.000 0.892 −0.108 1.05E−06183479294 183479402 183479884 YIPF1 54354660- 54354917- 54355137- Exc0.384 0.070 −0.314 1.42E−15 54354916 54355136 54355385 YME1L1 27425315-27431316- 27431415- Exc 0.897 0.774 −0.123 6.50E−26 27431315 2743141427434356 YTHDF2 29064851- 29068915- 29070499- Unc 0.891 0.896 0.0067.03E−01 29068914 29070498 29095440 YWHAB 43514528- 43516186- 43516384-Unc 0.100 0.103 0.003 7.26E−01 43516185 43516383 43530171 YWHAB43514528- 43516289- 43516384- Unc 0.151 0.150 −0.001 8.69E−01 4351628843516383 43530171 YY1AP1 155649304- 155650207- 155650248- Exc 0.9230.816 −0.107 4.12E−04 155650206 155650247 155657861 YY1AP1 155649304-155650173- 155650248- Exc 0.845 0.673 −0.172 1.08E−03 155650172155650247 155657861 ZBTB38 141122874- 141157110- 141157208- Unc 0.2140.213 0.000 9.84E−01 141157109 141157207 141161230 ZBTB38 141122874-141157085- 141157208- Unc 0.211 0.202 −0.009 7.68E−01 141157084141157207 141161230 ZBTB8OS 33093146- 33097428- 33097481- Exc 0.7130.581 −0.132 9.29E−05 33097427 33097480 33099245 ZC2HC1A 79610749-79624225- 79624342- Inc 0.062 0.219 0.156 3.70E−06 79624224 7962434179627455 ZC3H11A 203764923- 203765421- 203765730- Inc 0.201 0.555 0.3542.19E−13 203765420 203765729 203770702 ZC3H11A 203764923- 203765421-203765625- Inc 0.351 0.673 0.322 5.26E−13 203765420 203765624 203770702ZCCHC6 88932192- 88933873- 88933974- Exc 0.924 0.819 −0.104 2.10E−0488933872 88933973 88934498 ZCCHC6 88940430- 88941286- 88941407- Unc0.159 0.154 −0.005 9.59E−01 88941285 88941406 88943254 ZCCHC8 122974011-122975009- 122975115- Exc 0.977 0.868 −0.110 1.26E−03 122975008122975114 122977261 ZDHHC16 99213421- 99213556- 99213604- Exc 0.8100.587 −0.223 1.09E−12 99213555 99213603 99214470 ZDHHC20 21950795-21952800- 21952878- Inc 0.085 0.281 0.197 1.13E−23 21952799 2195287721955572 ZDHHC7 85015601- 85022369- 85022480- Exc 0.536 0.415 −0.1213.36E−08 85022368 85022479 85023909 ZEB1 31676196- 31676649- 31676728-Unc 0.233 0.235 0.002 9.27E−01 31676648 31676727 31749965 ZFAND182627350- 82629484- 82629524- Exc 0.621 0.382 −0.239 4.40E−12 8262948382629523 82630416 ZFAND5 74975704- 74978386- 74978523- Exc 0.559 0.450−0.109 4.90E−08 74978385 74978522 74979611 ZFAS1 47897108- 47897440-47897502- Exc 0.660 0.536 −0.125 2.58E−49 47897439 47897501 47905581ZFAT 135621123- 135622713- 135622899- Unc 0.792 0.792 0.000 9.29E−01135622712 135622898 135649703 ZFX 24170948- 24179832- 24179960- Unc0.264 0.261 −0.003 9.35E−01 24179831 24179959 24190831 ZMIZ1 81067329-81070681- 81070942- Exc 0.635 0.512 −0.124 1.40E−05 81070680 8107094181072398 ZMYM1 35545044- 35558921- 35559043- Unc 0.546 0.542 −0.0049.83E−01 35558920 35559042 35559514 ZMYM4 35734687- 35790961- 35791007-Exc 0.939 0.631 −0.309 4.74E−12 35790960 35791006 35824525 ZMYM520426331- 20436539- 20436607- Exc 0.911 0.689 −0.222 6.25E−05 2043653820436606 20437589 ZMYM5 20409830- 20411796- 20411962- Exc 0.914 0.557−0.358 1.76E−06 20411795 20411961 20425494 ZNF140 133660148- 133677573-133677640- Unc 0.502 0.500 −0.002 9.78E−01 133677572 133677639 133682095ZNF160 53589575- 53594666- 53594783- Exc 0.605 0.362 −0.244 3.05E−0453594665 53594782 53594889 ZNF207 30687987- 30688487- 30688535- Exc0.935 0.477 −0.459  1.66E−186 30688486 30688534 30689932 ZNF20730692507- 30693684- 30693777- Inc 0.629 0.872 0.243 9.12E−73 3069368330693776 30694790 ZNF217 52185804- 52188260- 52188393- Unc 0.836 0.835−0.001 9.72E−01 52188259 52188392 52192265 ZNF248 38145266- 38145363-38145461- Exc 0.985 0.762 −0.223 1.31E−04 38145362 38145460 38146112ZNF260 37006602- 37016057- 37016276- Unc 0.879 0.886 0.008 8.79E−0137016056 37016275 37019120 ZNF266 9530895- 9544741- 9544912- Unc 0.5640.568 0.004 8.76E−01 9544740 9544911 9545473 ZNF280D 56996466- 56999280-56999349- Exc 0.954 0.846 −0.108 6.55E−04 56999279 56999348 56999460ZNF280D 56996466- 56999280- 56999342- Exc 0.942 0.822 −0.120 9.46E−0456999279 56999341 56999460 ZNF3 99675057- 99677159- 99677280- Unc 0.8180.824 0.007 9.83E−01 99677158 99677279 99679257 ZNF346 176471535-176477752- 176477938- Unc 0.903 0.899 −0.004 9.51E−01 176477751176477937 176489058 ZNF37A 38383419- 38383859- 38384153- Unc 0.530 0.521−0.009 9.87E−01 38383858 38384152 38384465 ZNF384 6787627- 6787829-6787877- Exc 0.781 0.593 −0.188 2.07E−08 6787828 6787876 6788111 ZNF41958002966- 58003481- 58003580- Unc 0.617 0.624 0.007 9.78E−01 5800348058003579 58004223 ZNF426 9640313- 9641661- 9641744- Unc 0.898 0.9010.003 8.37E−01 9641660 9641743 9643520 ZNF512 27822921- 27823558-27823683- Exc 0.970 0.865 −0.106 1.55E−05 27823557 27823682 27824222ZNF516 74074513- 74082483- 74082551- Inc 0.831 1.000 0.169 7.19E−0874082482 74082550 74083421 ZNF529 37039225- 37042779- 37042880- Unc0.104 0.111 0.008 9.72E−01 37042778 37042879 37045571 ZNF532 56530983-56532536- 56532618- Inc 0.796 0.928 0.132 9.81E−04 56532535 5653261756532701 ZNF585B 37681053- 37689841- 37689957- Unc 0.897 0.896 −0.0019.20E−01 37689840 37689956 37697941 ZNF638 71558996- 71575557- 71577402-Unc 0.860 0.858 −0.001 9.30E−01 71575556 71577401 71582848 ZNF65599158319- 99159511- 99160118- Unc 0.765 0.762 −0.003 9.61E−01 9915951099160117 99161485 ZNF720 31765222- 31770678- 31770788- Exc 0.925 0.725−0.200 9.99E−04 31770677 31770787 31803950 ZNF75A 3355644- 3358313-3358837- Unc 0.782 0.778 −0.004 9.35E−01 3358312 3358836 3361752 ZNF767149317129- 149318137- 149318264- Unc 0.844 0.835 −0.009 9.22E−01149318136 149318263 149318350 ZSCAN32 3440518- 3443649- 3443815- Unc0.854 0.852 −0.001 9.08E−01 3443648 3443814 3447191 ZZZ3 78105288-78107069- 78107132- Exc 0.980 0.864 −0.117 2.20E−08 78107068 7810713178107206Differential Splicing Analysis to Identify Drug-Responding Sequencesfrom RNA Sequencing

For differential splicing analysis as shown in FIG. 21B, aCochran-Mantel-Haenszel test was applied followed by FDR(False-Discovery-Rate) correction. A FDR<0.1 and Δψ>=0.1 was consideredas an inclusion-response after treatment (FIG. 21B). Any triplet with aFDR<0.1 and Δψ≤=−0.1 was considered as an exclusion-response aftertreatment (FIG. 21B). Any exon triplet, whose ψ before-treatment was ina range from 0.1 to 0.9 and the ψ change after treatment was less than0.01, was considered to be an unchanged-response. For the Pearsoncorrelation analysis shown in FIG. 2C, the grey zone indicated a 9500confident interval. The p values were then adjusted by Bonferronicorrection. For the splicing strength comparison illustrated in FIG. 3C,the maximum entropy was compared amongst the inclusion, exclusion andunchanged groups at each splice Junction, using an unpaired Welch's ttest followed by Bonferroni correction. For the boxplots shown in FIG.3C, the middle lines inside boxes indicate the medians. The lower andupper hinges correspond to the first and third quartiles. Each boxextends to 1.5 times inter-quartile range (IQR) from the upper and lowerhinges respectively. Outliers were not shown. For RT-PCR comparison, anunpaired Student's t test was applied. For the distance comparison shownin FIG. 4B), the Kolmogorov-Smirnov (K-S) test was applied, where alltests were two-tailed. In all plots, the error bars indicate the 95%confident interval and the significance levels were marked by * havingp<0.05, ** p<0.01 and *** p<0.001, where the significance levels alwaysrefer to the adjusted p values if adjusted as described above. Trainingof CNN Model to Predict Potentially Responsive Genes

The CNN model (as shown in FIGS. 4A and 4B, and FIGS. 5A1, 5A2, 5B and5C) consisted of two layers of convolutions with a total of 2.50 milliontrainable parameters optimized for predicting splicing changes afterbeing trained using RNASeq values for effect on exon triplet splicingafter Compound (I) treatment.

The two convolutional layers and one hidden layer (see FIGS. 5A1 and5A2) were trained using the Basset framework⁴¹. The training setconsisted of 178 inclusion-responded, 476 exclusion-responded and 268unchanged exon triplets. The validation sets consisted of 51inclusion-responded, 136 exclusion-responded and 76 unchanged exontriplets. The test set consisted of 25 inclusion-responded, 68exclusion-responded and 38 unchanged exon triplets. The three sets wereassigned randomly in Python using seed of 122. For each exon-triplet,the sequences consisting of an exonic 25 nucleotide sequence and anintronic 75 nucleotide sequence within the UI₁, I₁X, XI₂ and I₂D regions(see FIG. 2A) were concatenated and then one-hot coded into an inputmatrix with a size of 4×400. The first round of convolution was appliedwith fifty 4×5 weight matrices, converting the input matrix into a50×396 convoluted matrix, in which each row represented the convolutionof one weight matrix.

The convolution matrix was nonlinearly transformed using a rectifiedlinear unit (ReLU) function, with the maximum pool stage taking themaximum of two adjacent positions of each row, shrinking the outputmatrix to a size of 50×198. The second round of matrix convolution thenapplied fifty 4×2 weight matrices, followed by the same ReLUtransformation and maximum pool of the first round. The output wasconverted to a 1×500 matrix to initiate the hidden layer, where a fullyconnected network was built with 90% dropout rate. The output from thehidden layer was ReLU transformed again and was then linearlytransformed into a vector of three values, representing the threedifferent treatment responses. The final sigmoid nonlinearity mappedeach element in the vector to a value between 0 and 1, considered as theprobability of small molecule splicing modulator compoundresponsiveness. In each Epoch of training, an average of the area underthe curve (AUC) was measured on the validation set across the predictionof three treatment responses. The training and validation loss in termsof binary cross-entropy were measured on the training set and validationset respectively. The training process stopped if there was noimprovement in the AUC average over 10 consecutive Epochs. In thisstudy, training was stopped at the 12^(th) Epoch to avoid overfitting(see FIG. 5B).

The CNN model obtained an average accuracy for an Area-Under-Curve (AUC)of 0.82 (as shown in FIG. 5C), identifying 39 5-mer CNN Motifs (as shownin FIG. 6A1-6A7) that suggest genes having similar motifs would also beaffected by Compound (I) splicing modulation. The 39 CNN Motifs wereidentified based on their higher probability to cause a splicingreaction in the presence of Compound (I), yielding a prediction ofwhether the isoform produced will be the result of either an exclusionof an exon or inclusion of an exon or poison exon or whether there willbe no change in the isoform produced. The 39 CNN Motifs present inwildtype or mutant genes described herein may cause changes or no changein isoform results in other genes not described herein depending on thestructure of the small molecule splicing compound tested.

Without being limited by theory, the 39 CNN Motifs obtained using theCNN Model described herein may suggest other equivalents that may beobtained within the scope of the deep learning algorithm underlying theCNN Model, enabling others of ordinary skill in the art to predict orallow the prediction of the effect of other small molecule splicingcompounds to modulate the production of one or more mature RNA isoformsfrom other wildtype or mutant gene transcripts than those described orpredicted herein. In other words, the in vitro and in vivo minigene dataprovided herein demonstrates that the use of all 39 CNN Motifs in theCNN Model were sufficient and efficient to make correct and accuratepredictions.

CNN Motif Ranking

The 39 CNN Motifs may be ranked according to a predicted probability formodulating the production of one or more mature RNA isoforms from awildtype or mutant gene transcript. Two analytic methods were used torank the degree of Motif probability to predict an effect on splicing inthe presence of a small molecule splicing compound. In the firstinstance, the analytic method used reset each Motifs activationprobability level to the average level of all Motif activations. Asshown in FIGS. 3A1-3A2, the 12 CNN Motifs having AUC changes greaterthan 0.1 were identified and ordered according to the AUC change beforeand after the reset. In the second instance, the analytic method usedreset each Motifs activation level to zero. As shown in FIGS. 3B1-3B2,the 13 CNN Motifs having AUC changes greater than 0.05 were identifiedand ordered according to the AUC change before and after the reset.

The 39 CNN Motifs may be ranked according to positional importance formodulating the production of one or more mature RNA isoforms from awildtype or mutant gene transcript. Two analytic methods were used torank the positional importance of each Motif to predict an effect onsplicing in the presence of a small molecule splicing compound. In thefirst instance, the AUC analytic method used reset each nucleotide'sposition activation level to the average activation level of thatposition. As shown in FIG. 3A3, the positional importance for the 12 CNNMotifs was ranked by the AUC change before and after the reset. In thesecond instance, the AUC analytic method used the highest activation ofeach nucleotide position to identify and order the Motifs. As shown inFIG. 3B3, the Motif positional importance for the 13 CNN Motifs wasranked according to the highest activation of each nucleotide positionas shown in the heatmap results.

Moreover, without theoretical limitation, the ranking of the 39 Motifsused in the CNN Model according to the description herein and otherembodiments may be ordered by those of ordinary skill in the art using avariety of analytic and mathematic modeling to predict or allow theprediction of the effect of other small molecule splicing compounds tomodulate the production of one or more mature RNA isoforms from otherwildtype or mutant gene transcripts than those described or predictedherein.

Positional Importance in the CNN Model

To examine each motif contribution in classification, the validation setwas used as model input. For each motif whose positional importance wasto be measured, the position-wise output of the first convolutionallayer from that motif was manually set as the mean of all theconvolutional output. The model was then used without tuning otherparameters and the new loss, measured by binary cross-entropy, wascalculated. The importance of the motif at that tuned position wasmeasured as the difference between the new loss of the model and theoriginal loss of the model. All the positions of that motif weresimilarly investigated.

Determining the Standardized Probability from CNN Model Prediction

To determine the drug response class (inclusion, exclusion or unchanged)using the CNN Model prediction, the raw prediction score from the Modelwas standardized. For each class, a cutoff representing 95% specificityfor that response was identified on the validation set. The intermediatescore of each class was calculated as the raw prediction score dividedby the cutoff of that response class. The standardized probability foreach response was then calculated as the intermediate score divided bythe sum of intermediate scores of the three classes.

Identification of Enrichment Motif Using K-Mer Enrichment Analysis

The sequences of adjacent nucleotides from the −3 to +7 position of the5′ splice sites of the middle exons for inclusion, exclusion andunchanged exon triplets were extracted. For each class response, 5-merenrichment was estimated against the other two classes usingDiscriminative Regular Expression Motif Elicitation (DREME) from THEMEME Suite (PMID: 21543442) with the parameter “-p, -n, -dna -e 0.05 and-k 5”.

The 5-mer sequence enrichment analysis of adjacent nucleotides from the−3 to +7 position in the Exon X 5′ splice site also agreed with the 39CNN Motifs identified by the CNN model (as shown in FIG. 6A1-6A7). Theseresults suggest that 5′splice site sequences containing the CNN Motifsare predictively involved in non-canonical U1-5′splice site interaction.

CNN Model Splice Site Strength Analysis

To determine the effect of the CNN Motifs on the splicing of responsivetriplets, the strength of the four splice sites UI₁, I₁X, XI₂ and I₂Dwithin the triplets was evaluated. Splice site strength for each motifwas measured using a maximum entropy model⁷⁷. As described, themeasurement used was either the short sequence of 9 nucleotides and 23nucleotides for the flanking splice junctions, as determined from the 5′or 3′ end, respectively. The resulting analysis found that exon tripletswith inclusion responses had significantly lower strength in the Exon X5′ splice site compared to the exon triplets with unchanged response (asshown in FIG. 3C). Consistent with previous findings that support therole of this class of splicing modulator compounds in promoting therecruitment of U1 snRNP in non-canonical ending exons^(46,56), thesedata suggest that weak 5′ splice sites are more sensitive to treatmentwith Compound (I).

CNN Model Prediction

To evaluate the reproducibility of the model, random initialization ofthe training process was implemented 1,000 times. It was found that theperformance of all models was tightly distributed and aligned with theoriginal model (FIG. 12A). In addition, all of the top 10 first-layerfilters contributing to the performance of the CNN model were highlycorrelated with those of the 1,000 random-initialized models (averagePearson correlation R2=0.55, FIG. 12B), suggesting that the deeplearning framework was robust.

The 39 5-mer motifs (CNN Motifs) were identified from the first layer ofthe CNN model were identified (FIGS. 6A1-6A7). The treatment responsewas not determined by any of these motifs independently, all 39 CNNMotifs are used in the CNN Model to interrogate genes of interest. Assuch, the CNN model utilizes the synergistic effect of all 39 Motifs ona given sequence to make the Class decision. Thirteen motifs (see FIGS.3B1-3B2) explained 92.62% of the AUC, each of which altered more than0.105 of AUC for at least one class of prediction (FIG. 5C). Analysis ofthese motifs revealed that the sequence in proximity to, and in manycases encompassing, the 5′ splice site of the middle exon had thelargest influence in modulating treatment response (FIGS. 3A, 3B and3C). These results emphasized the importance of the 5′ splice site indetermining treatment outcome. In silico saturation mutagenesis furthersupported these findings, revealing that base contribution to thetreatment outcomes peaked around the 5′ splice sites of the middleexons, with distinct patterns amongst sequences with inclusion,exclusion and unchanged responses (FIG. 3C).

Table 17 lists the motifs (Motif) shown in FIGS. 6A1-6A7, with constantand most dominant nucleotides as shown in the LOGO plot. The 39 CNNMotifs were those most frequent 5-mer sequences (5-mer) predicted by theCNN Model to affect splicing in the presence of Compound (I) toward aninclusion, exclusion or unchanged Effect.

TABLE 17 Motif 5-Mer SEQ ID NO. Effect 01 CTTAG 25 Unchanged 02 NNAGC 26Exclusion 03 NCAGA 27 Exclusion 04 CCCTT 28 Inclusion 05 TNNCT 29Exclusion 06 GCAGA 30 Unchanged 09 TNTGA 31 Exclusion 10 TGAGC 32Exclusion 12 CTCTC 33 Exclusion 14 TNNNT 34 Inclusion 15 TTTTT 35Inclusion 16 ATGGN 36 Unchanged 17 TCTCA 37 Unchanged 18 AAGCT 38Inclusion 20 GTCAT 39 Exclusion 21 GAGAG 40 Exclusion 22 AGGAN 41Unchanged 23 AGACC 42 Inclusion 25 AAGGT 43 Inclusion 26 GATTA 44Inclusion 27 TCTTT 45 Unchanged 28 NNAGN 46 Inclusion 29 TCGTG 47Exclusion 31 ANGAA 48 Exclusion 32 TTAAA 49 Inclusion 33 AGACT 50Unchanged 34 GGGTG 51 Inclusion 35 TTCCC 52 Inclusion 37 AGTNA 53Unchanged 38 TATGT 54 Exclusion 40 GGGAA 55 Exclusion 41 NTGNN 56Exclusion 42 NTCCC 57 Exclusion 43 CAGGC 58 Exclusion 44 NTGTN 59Exclusion 46 NTCCT 60 Unchanged 47 AACCT 61 Exclusion 48 ACTCN 62Unchanged 49 CTGTA 63 Inclusion

Identification of ClinVar Therapeutic Targets Harboring Disease-CausingMutations Amenable to Compound (I) Splicing Modulation

As shown in FIG. 4A, from 89,642 potential CV-pMUTs within 5 kb upstreamor downstream of the mutated site, SpliceAI scores identified 17,956(20.03%) splice site mutations that had the potential to disruptpre-mRNA splicing in the gene and result in a disease. Out of those17,956 CV-pMUTs, there were 14,272 (79.48%) leading to splicingdisruption of the Ensembl-annotated splice sites (GRCh37 version 75).These CV-pMUT disrupting annotated splice sites were then used to trainthe CNN model to predict splicing alterations in mutated splice sitesthat could be corrected by Compound (I) treatment.

As shown in FIG. 4B, the CV-pMUTs disrupting annotated splice sitesdemonstrated that the identified flanking regions UI₁, I₁X, XI₂ and I₂Dwere significantly closer to the splice junction than the CV-pMUTs thathad no effect in disrupting annotated splice sites. Since about 98% ofthem were within 75 nucleotides of the splice site junction, theflanking regions were determined to include most of the targetablepathogenic splicing alterations for use in training the CNN model.

As illustrated in FIG. 4A, amongst the 14,272 CV-pMUTs predicted todisrupt annotated splice sites (corresponding to 11,616 exon triplets in1,970 genes), the CNN model predicted that the altered splicing of 234CV-pMUTs (1.64%) found in 295 exon triplets (2.54%) in 174 genes (8.83%)could be rescued by splicing modulation, toward either or both exoninclusion and exon exclusion, resulting from Compound (I) treatment.

SpliceAI Prediction for ClinVar Pathogenic Mutations

The VCF file recording ClinVar (version 20190325) mutations wasdownloaded. The pathogenic/likely pathogenic mutations were extractedand fed to SpliceAI (https://github.com/illumina/SpliceAI). In theprediction from SpliceAI, any mutation with any SpliceAI score greaterthan 0.2 was considered to be the result of altering splicing. As shownin Table 19, those mutations, together with the influenced splicejunction (ISJ) and SpliceAI score were recorded.

Rescue Definition and Prediction

For an exon triplet, the coordinates of the two flanking domains of themiddle exon for an exon triplet were compared to those ISJs discoveredby SpliceAI. If either domain overlapped with an ISJ and the SpliceAIscore indicated a splicing gain, the exon triplet was considered tolikely promote exon inclusion as a result of the corresponding mutation.On the other hand, a 5′ splice site of the middle exon overlapping withan ISJ and having a SpliceAI score that indicated a splicing loss, theexon triplet was considered to likely promote exon skipping as a resultof the corresponding mutation.

Three possible rescue outcomes were considered: 1) The mutated exontriplet was predicated (by SpliceAI) to cause exon skipping and the CNNmodel predicted an inclusion response after Compound (I) treatment; or,2) The mutated exon triplet was predicted (by SpliceAI) to promote exoninclusion and the CNN model predicted an exclusion response afterCompound (I) treatment; or, 3) the mutated exon triplet generated apre-mature termination codon (PTC) inside the middle exon and the CNNmodel predicted an exclusion response after Compound (I) treatmentwithout a reading frameshift after exclusion.

Allele Frequency From gnomAD

VCF files for both human exome and genome sequencing were downloadedfrom gnomAD (v2.1.1). The corresponding ClinVar mutations were locatedin the VCF files via their SNP IDs. If a short variant was found only inthe exome or only in the genome sequencing VCF, the reported minorallele frequency was then used. If a short variant was found in both theexome and genome sequencing, the combined frequency was calculated as(AC1+AC2)/(AN1+AN2), where AC1 and AC2 were the allele counts for exomeand genome sequencing, respectively, and AN1 and AN2 were the totalsample sizes for exome and genome sequencing, respectively.

As described herein, wildtype genes were identified by RNA sequencingand ClinVar mutated genes were predicted by SpliceAI scores and the CNNmodel to harbor a mutation that will cause a splicing defect wereanalyzed, as described herein, to determine whether they could beresponsive to Compound (I) splicing modulation. The CNN Model was usedto predict whether the ClinVar SpliceAI identified splicing defect couldbe rescued by treatment with Compound (I) modulation of splicing towardeither or both exon inclusion and exon exclusion. As described herein,certain genes were responsive to modulation of splicing as a result oftreatment with Compound (I).

Table 18 lists for each mutated Gene (identified by ClinVar and Alleleidentification numbers) and associated Introns and Exon (where Intron 1is upstream of the affected Exon and Intron 2 is downstream), predictedby SpliceAI scores based on frequency of occurrence (gnomAD Freq) andthe CNN model, as described herein, that may be modulated by Compound(I) toward either or both exon inclusion and exon exclusion (Rescue).

TABLE 18 Clin gnomAD Gene Rescue VAR Allele Freq Intron 1 Exon Intron2ABCA4 inclusion 236104 237676 −1 94502345- 94502701- 94502907- 94502700 94502906  94505598  ABCC9 inclusion 31947 40612 3.99E−06 21991105-21995248- 21995406- 21995247  21995405  21997416  ABCC9 inclusion 3194640611 −1 21991105- 21995248- 21995406- 21995247  21995405  21997416 ACADSB inclusion 9199 24238 2.95E−05 124810703- 124812577- 124812677-124812576  124812676  124813210  ADAM10 inclusion 88840 94409 −158904191- 58913670- 58913821- 58913669  58913820  58919898  AGKinclusion 209129 205751 1.42E−05 141313979- 141315271- 141315366-141315270  141315365  141321531  ALDH3A2 inclusion 189079 186958 −119559888- 19561034- 19561176- 19561033  19561175  19564439  ALDH3A2inclusion 189079 186958 −1 19559888- 19561058- 19561176- 19561057 19561175  19564439  ALMS1 inclusion 191112 188916 −1 73646447- 73649985-73650103- 73649984  73650102  73651557  ANTXR2 inclusion 2598 17637 −180899329- 80905032- 80905125- 80905031  80905124  80905972  APCinclusion 411344 394701 −1 112116601- 112136976- 112137081- 112136975 112137080  112151191  APC inclusion 411344 394701 −1 112128227-112136976- 112137081- 112136975  112137080  112151191  APC inclusion411344 394701 −1 112128227- 112136976- 112137081- 112136975  112137080 112145822  APC inclusion 433614 427251 −1 112146009- 112151192-112151291- 112151191  112151290  112154662  APC inclusion 486792 473576−1 112151291- 112154663- 112155042- 112154662  112155041  112157592  APCinclusion 411416 394347 −1 112151291- 112154663- 112155042- 112154662 112155041  112157592  APC inclusion 428128 419618 −1 112157689-112170648- 112170863- 112170647  112170862  112173249  APC inclusion428128 419618 −1 112164670- 112170648- 112170863- 112170647  112170862 112173249  ARMC9 inclusion 427935 419011 3.98E−06 232137792- 232141349-232141489- 232141348  232141488  232143094  ASAH1 inclusion 55908 70551−1 17916974- 17917081- 17917213- 17917080  17917212  17918885  ASPMinclusion 402180 389111 −1 197062392- 197063214- 197063311- 197063213 197063310  197065127  ASPM inclusion 210353 206745 −1 197091726-197093240- 197093462- 197093239  197093461  197093999  ASPM inclusion21572 34424 −1 197094086- 197094176- 197094322- 197094175  197094321 197097619  ATM inclusion 3044 18083 4.39E−05 108124767- 108126942-108127068- 108126941  108127067  108128207  ATM inclusion 181974 1804832.78E−05 108183226- 108186550- 108186639- 108186549  108186638 108186737  ATM inclusion 3035 18074 1.59E−05 108150336- 108151722-108151896- 108151721  108151895  108153436  ATM inclusion 230851 2339094.01E−06 108098616- 108099905- 108100051- 108099904  108100050 108106396  ATM inclusion 230851 233909 4.01E−06 108098616- 108099905-108100051- 108099904  108100050  108114679  ATM inclusion 135778 1394903.99E−06 108202285- 108202606- 108202765- 108202605  108202764 108203488  ATRX inclusion 560933 552266 −1 76907844- 76909588- 76909691-76909587  76909690  76912049  BBS4 inclusion 585184 576240 −1 73002121-73004585- 73004649- 73004584  73004648  73009118  BBS4 inclusion 585184576240 −1 73002121- 73004585- 73004649- 73004584  73004648  73007631 BFSP1 inclusion 425558 413913 0.00E+00 17475675- 17477583- 17477669-17477582  17477668  17479464  BMPR2 inclusion 425729 414116 −1203242274- 203329532- 203329703- 203329531  203329702  203332241  BRCA1inclusion 37604 46160 3.19E−05 41223256- 41226348- 41226539- 41226347 41226538  41228504  BRCA1 inclusion 37604 46160 3.19E−05 41223256-41226348- 41226539- 41226347  41226538  41277287  BRCA1 inclusion 1766032699 1.20E−05 41256974- 41258473- 41258551- 41258472  41258550 41276033  BRCA1 inclusion 17660 32699 1.20E−05 41256974- 41258473-41258551- 41258472  41258550  41262481  BRCA1 inclusion 55131 69798 −141234593- 41242961- 41243050- 41242960  41243049  41251791  BRCA1inclusion 55131 69798 −1 41234593- 41242961- 41243050- 41242960 41243049  41246760  BRCA1 inclusion 55131 69798 −1 41234593- 41242961-41243050- 41242960  41243049  41243451  BRCA1 inclusion 55131 69798 −141234593- 41242961- 41243050- 41242960  41243049  41247862  BRCA1inclusion 54471 69138 −1 41256974- 41258473- 41258551- 41258472 41258550  41276033  BRCA1 inclusion 54471 69138 −1 41256974- 41258473-41258551- 41258472  41258550  41262481  BRCA1 inclusion 54471 69138 −141256974- 41258473- 41258551- 41258472  41258550  41267742  BRCA2inclusion 38215 46771 4.03E−06 32953653- 32953887- 32954051- 32953886 32954050  32954143  BRCA2 inclusion 51711 66379 −1 32899322- 32900238-32900288- 32900237  32900287  32900378  BRCA2 inclusion 52058 66726 −132900420- 32900636- 32900751- 32900635  32900750  32903579  CA5Ainclusion 127088 132598 1.66E−04 87935581- 87936031- 87936127- 87936030 87936126  87938391  CAPN3 inclusion 523316 514049 −1 42678484- 42679951-42680085- 42679950  42680084  42681125  CD3D inclusion 180674 1788427.96E−06 118210210- 118211090- 118211309- 118211089  118211308 118211584  CD3D inclusion 180674 178842 7.96E−06 118210622- 118211090-118211309- 118211089  118211308  118213267  CD3D inclusion 180674 1788427.96E−06 118210210- 118211090- 118211309- 118211089  118211308 118213267  CDH1 inclusion 185583 184420 −1 68849663- 68853183- 68853329-68853182  68853328  68855903  CDH23 inclusion 45989 55154 8.05E−0673544178- 73544648- 73544858- 73544647  73544857  73545387  CERKLinclusion 438052 431648 −1 182413332- 182413407- 182413585- 182413406 182413584  182414360  CFTR inclusion 53750 68418 7.09E−06 117251863-117254667- 117254768- 117254666  117254767  117267575  CFTR inclusion35857 44521 7.08E−06 117243837- 117246728- 117246808- 117246727 117246807  117250572  CFTR inclusion 54012 68679 −1 117171169-117174330- 117174420- 117174329  117174419  117175301  CHD7 inclusion520773 511761 −1 61754612- 61757423- 61757623- 61757422  61757622 61757808  CLCN1 inclusion 447078 441048 1.41E−05 143021586- 143027865-143027991- 143027864  143027990  143028324  CLMP inclusion 50384 595063.98E−06 122944483- 122945410- 122945559- 122945409  122945558 122953792  CLMP inclusion 50384 59506 3.98E−06 122944483- 122945410-122945552- 122945409  122945551  122953792  CLMP inclusion 50384 595063.98E−06 122944483- 122945410- 122945525- 122945409  122945524 122953792  CLN3 inclusion 56265 70904 4.00E−06 28498863- 28498983-28499063- 28498982  28499062  28500610  CLN3 inclusion 56265 709044.00E−06 28498863- 28498983- 28499063- 28498982  28499062  28499911 CLN3 inclusion 56265 70904 4.00E−06 28498863- 28498983- 28499063-28498982  28499062  28502802  CLN3 inclusion 56265 70904 4.00E−0628498863- 28498983- 28499063- 28498982  28499062  28500610  CNGB3inclusion 427674 417119 −1 87656915- 87660029- 87660116- 87660028 87660115  87666239  COG6 inclusion 493009 485965 7.10E−06 40254183-40256308- 40256402- 40256307  40256401  40261639  COL11A1 inclusion547210 537669 0.00E+00 103364330- 103364497- 103364551- 103364496 103364550  103377714  COL3A1 inclusion 101376 107122 −1 189863046-189863400- 189863445- 189863399  189863444  189864010  COL4A3 inclusion551759 541906 −1 228125834- 228128496- 228128661- 228128495  228128660 228131132  COL4A5 inclusion 38768 47373 5.55E−06 107863657- 107865033-107865123- 107865032  107865122  107865905  COL4A5 inclusion 587202578111 −1 107827756- 107829845- 107829978- 107829844  107829977 107834287  COL4A5 inclusion 587163 578120 −1 107829978- 107834288-107834462- 107834287  107834461  107834790  COL4A5 inclusion 24409 35750−1 107834462- 107834791- 107834875- 107834790  107834874  107838738 COL4A5 inclusion 24530 35871 −1 107850123- 107858141- 107858255-107858140  107858254  107863488  COL4A5 inclusion 24550 35891 −1107863657- 107865033- 107865123- 107865032  107865122  107865905  COL4A5inclusion 24696 36037 −1 107920864- 107923909- 107923982- 107923908 107923981  107924114  COL4A5 inclusion 24773 36114 −1 107936156-107938037- 107938152- 107938036  107938151  107939526  COL4A5 inclusion24782 36123 −1 107938152- 107938497- 107938670- 107938496  107938669 107939526  COL5A2 inclusion 213101 209548 −1 189926342- 189927591-189927645- 189927590  189927644  189927735  CSTB inclusion 55958 70597−1 45194212- 45194539- 45194641- 45194538  45194640  45196084  CTNSinclusion 556587 548124 −1 3543562- 3558515- 3558647- 3558514  3558646 3559780  CTU2 inclusion 585016 576071 9.29E−06 88779314- 88779720-88779856- 88779719  88779855  88780054  CUBN inclusion 56321 70960 −117142239- 17145124- 17145237- 17145123  17145236  17146417  CWC27inclusion 426071 414475 3.80E−06 64079807- 64081308- 64081407- 64081307 64081406  64082350  CYBB inclusion 10933 25972 −1 37639376- 37642743-37642854- 37642742  37642853  37651227  DCX inclusion 158456 169903 −1110644559- 110653263- 110653649- 110653262  110653648  110655365  DCXinclusion 158456 169903 −1 110644559- 110653263- 110653649- 110653262 110653648  110653981  DCX inclusion 158456 169903 −1 110644559-110653263- 110653649- 110653262  110653648  110655197  DGKE inclusion548648 539159 −1 54923171- 54925283- 54925427- 54925282  54925426 54926056  DGUOK inclusion 214286 210897 4.95E−05 74174034- 74177712-74177860- 74177711  74177859  74184251  DGUOK inclusion 214286 2108974.95E−05 74174034- 74177754- 74177860- 74177753  74177859  74185272 DGUOK inclusion 214286 210897 4.95E−05 74174034- 74177728- 74177860-74177727  74177859  74185272  DMD inclusion 501566 492990 −1 32717411-32827610- 32827729- 32827609  32827728  32834584  DNAH5 inclusion 228251229258 1.99E−05 13829814- 13830135- 13830323- 13830134  13830322 13830705  DNAH5 inclusion 572293 564698 1.99E−05 13701546- 13708232-13708445- 13708231  13708444  13714513  DNAH9 inclusion 617523 6088911.45E−04 11543702- 11547948- 11548017- 11547947  11548016  11550388 DYNC2H1 inclusion 437419 430981 4.15E−06 102996025- 102999639-102999735- 102999638  102999734  103004283  DYNC2LI1 inclusion 518440509032 1.32E−05 44023935- 44027980- 44028057- 44027979  44028056 44028777  EBF3 inclusion 488452 481314 −1 131676114- 131755522-131755591- 131755521  131755590  131757197  EP300 inclusion 378053380144 −1 41560135- 41562603- 41562671- 41562602  41562670  41564452 F10 inclusion 12059 27098 −1 113798410- 113801693- 113801801- 113801692 113801800  113803229  F13A1 inclusion 16524 31563 3.98E−06 6146006-6152046- 6152183- 6152045  6152182  6167690  FBN1 inclusion 437420430986 −1 48725186- 48726791- 48726911- 48726790  48726910  48729157 FUT8 inclusion 545467 535727 −1 66188740- 66190865- 66191042- 66190864 66191041  66199948  G6PC inclusion 214465 211810 1.77E−05 41059646-41061320- 41061436- 41061319  41061435  41062931  GAA inclusion 188044185936 4.03E−06 78082628- 78083744- 78083855- 78083743  78083854 78084525  GABRG2 inclusion 433102 426665 −1 161529680- 161530895-161531033- 161530894  161531032  161569169  GABRG2 inclusion 433102426665 −1 161528324- 161530895- 161531033- 161530894  161531032 161569169  GCK inclusion 36224 44888 −1 44189664- 44190555- 44190675-44190554  44190674  44191869  GLA inclusion 180842 179870 −1 100653556-100653773- 100653935- 100653772  100653934  100654731  GLA inclusion180842 179870 −1 100653556- 100653773- 100653935- 100653772  100653934 100655653  GNB5 inclusion 268098 263624 −1 52442123- 52446137- 52446274-52446136  52446273  52471964  GNPTAB inclusion 397556 384468 3.99E−06102174400- 102179790- 102179996- 102179789  102179995  102182325  GNPTABinclusion 2761 17800 −1 102164936- 102173930- 102174065- 102173929 102174064  102174334  GPR143 inclusion 10517 25556 −1 9716707- 9727372-9727467- 9727371  9727466  9728756  GPX4 inclusion 140615 1503203.59E−05 1105510- 1105657- 1105809- 1105656  1105808  1106240  GRHPRinclusion 548673 539143 3.98E−06 37425992- 37426535- 37426652- 37426534 37426651  37428480  GRN inclusion 599616 590962 −1 42427709- 42428918-42429164- 42428917  42429163  42429382  GRN inclusion 599616 590962 −142428829- 42428918- 42429164- 42428917  42429163  42429382  GUCY2Cinclusion 31604 40288 3.99E−06 14822768- 14825807- 14825893- 14825806 14825892  14827558  GYPA inclusion 17714 32753 3.60E−05 145039906-145040839- 145040935- 145040838  145040934  145041642  HBB inclusion36337 45001 1.03E−04 5248030- 5248160- 5248270- 5248159  5248269 5248741  IDH1 inclusion 375891 362770 0.00E+00 209110149- 209113093-209113385- 209113092  209113384  209116153  IDH1 inclusion 375893 3627720.00E+00 209110149- 209113093- 209113385- 209113092  209113384 209116153  IFT57 inclusion 506288 497913 −1 107886712- 107910368-107910491- 107910367  107910490  107925474  IL36RN inclusion 40005 485189.55E−04 113817045- 113818429- 113818515- 113818428  113818514 113819700  KDSR inclusion 427791 418321 2.83E−05 60999135- 61002490-61002592- 61002489  61002591  61006032  KIAA0586 inclusion 208813 2053741.38E−05 58924698- 58925191- 58925264- 58925190  58925263  58926560 KIAA0586 inclusion 208813 205374 1.38E−05 58924698- 58925191- 58925264-58925190  58925263  58927703  KIAA1109 inclusion 487550 480599 −1123145833- 123147862- 123147991- 123147861  123147990  123150275  KIF14inclusion 503567 495007 −1 200530009- 200534197- 200534382- 200534196 200534381  200534572  KIT inclusion 13843 28882 −1 55594094- 55594177-55594288- 55594176  55594287  55595500  KMT2D inclusion 547418 537993 −149441853- 49442442- 49442553- 49442441  49442552  49442887  KRIT1inclusion 590717 581356 −1 91843294- 91843925- 91844092- 91843924 91844091  91851215  KRIT1 inclusion 590718 581357 −1 91843294- 91843925-91844092- 91843924  91844091  91851215  LAMB3 inclusion 14543 29582 −1209806122- 209806415- 209806479- 209806414  209806478  209807791  LDLRinclusion 252233 246528 7.99E−06 11230910- 11231046- 11231199- 11231045 11231198  11233849  LIPA inclusion 203361 199794 1.03E−04 90975767-90982268- 90982340- 90982267  90982339  90983440  LMNA inclusion 519180509123 −1 156106228- 156106712- 156107024- 156106711  156107023 156107444  LMNA inclusion 519180 509123 −1 156106820- 156106904-156107024- 156106903  156107023  156107444  LMNA inclusion 519180 509123−1 156106820- 156106904- 156107024- 156106903  156107023  156108278 LMNA inclusion 66854 77751 −1 156106228- 156106712- 156107024-156106711  156107023  156107444  LMNA inclusion 66854 77751 −1156106820- 156106904- 156107024- 156106903  156107023  156107444  LMNAinclusion 66854 77751 −1 156106820- 156106904- 156107024- 156106903 156107023  156108278  MCFD2 inclusion 2865 17904 1.19E−05 47135109-47136162- 47136317- 47136161  47136316  47139681  MCFD2 inclusion 286517904 1.19E−05 47135109- 47136162- 47136317- 47136161  47136316 47143119  MCFD2 inclusion 2865 17904 1.19E−05 47135109- 47136162-47136317- 47136161  47136316  47142861  MCFD2 inclusion 2865 179041.19E−05 47135109- 47136162- 47136317- 47136161  47136316  47168710 MLH1 inclusion 90285 95759 −1 37048555- 37053311- 37053354- 37053310 37053353  37053501  MLH1 inclusion 90285 95759 −1 37050397- 37053311-37053354- 37053310  37053353  37053501  MLH1 inclusion 90415 95889 −137056036- 37058997- 37059091- 37058996  37059090  37061800  MLH1inclusion 90415 95889 −1 37056036- 37058997- 37059091- 37058996 37059090  37067127  MLH1 inclusion 89616 95090 −1 37056036- 37061801-37061955- 37061800  37061954  37067127  MLH1 inclusion 89616 95090 −137059091- 37061801- 37061955- 37061800  37061954  37067127  MLH1inclusion 89979 95453 −1 37089175- 37090008- 37090101- 37090007 37090100  37090394  MMAB inclusion 218326 215033 −1 110002982-110006575- 110006669- 110006574  110006668  110011151  MMAB inclusion218326 215033 −1 110002982- 110006575- 110006669- 110006574  110006668 110009453  MMAB inclusion 218326 215033 −1 110002982- 110006575-110006669- 110006574  110006668  110007776  MPC1 inclusion 35561 44234−1 166778942- 166779462- 166779595- 166779461  166779594  166780282 MSH2 inclusion 483664 472825 −1 47690294- 47693797- 47693948- 47693796 47693947  47698103  MSH2 inclusion 483724 472839 −1 47693948- 47698104-47698202- 47698103  47698201  47702163  MTM1 inclusion 158960 169974 −1149765035- 149783062- 149783173- 149783061  149783172  149787510  MTM1inclusion 158960 169974 −1 149767151- 149783062- 149783173- 149783061 149783172  149787510  MTM1 inclusion 158966 169981 −1 149765035-149783062- 149783173- 149783061  149783172  149787510  MTM1 inclusion158966 169981 −1 149767151- 149783062- 149783173- 149783061  149783172 149787510  MYBPC3 inclusion 454301 461685 −1 47365176- 47367758-47367922- 47367757  47367921  47368177  MYO7A inclusion 228280 2313857.19E−06 76891528- 76892426- 76892636- 76892425  76892635  76892996  NF1inclusion 480206 478059 −1 29486112- 29490204- 29490395- 29490203 29490394  29508439  NF1 inclusion 480206 478059 −1 29486112- 29490204-29490395- 29490203  29490394  29496908  NF1 inclusion 428998 420767 −129509684- 29527440- 29527614- 29527439  29527613  29528054  NF1inclusion 431976 426213 −1 29546137- 29548868- 29548948- 29548867 29548947  29550461  NF1 inclusion 220498 222614 −1 29626625- 29652838-29653271- 29652837  29653270  29654516  NF1 inclusion 220498 222614 −129592358- 29652838- 29653271- 29652837  29653270  29654516  NF1inclusion 220498 222614 −1 29645583- 29652838- 29653271- 29652837 29653270  29654516  NF1 inclusion 185354 184694 −1 29653271- 29654517-29654858- 29654516  29654857  29657313  NIPBL inclusion 446431 439877 −136971139- 36972047- 36972144- 36972046  36972143  36975877  NPHP1inclusion 3510 18549 1.06E−05 110919275- 110920625- 110920713-110920624  110920712  110922264  NPHP1 inclusion 3510 18549 1.06E−05110919275- 110920625- 110920710- 110920624  110920709  110922096  NPHP1inclusion 3510 18549 1.06E−05 110919275- 110920625- 110920710-110920624  110920709  110922264  NPHP1 inclusion 3510 18549 1.06E−05110919275- 110920625- 110922308- 110920624  110922307  110922628  NPHP1inclusion 3510 18549 1.06E−05 110919275- 110920625- 110920713-110920624  110920712  110922096  NR3C2 inclusion 8564 23603 −1149116014- 149181130- 149181270- 149181129  149181269  149356255  NR3C2inclusion 8564 23603 −1 149116014- 149181130- 149181270- 149181129 149181269  149289416  NSD1 inclusion 573155 560277 5.96E−05 176710930-176715820- 176715927- 176715819  176715926  176718954  OCA2 inclusion965 16004 1.19E−05 28231790- 28234747- 28234813- 28234746  28234812 28259921  OCA2 inclusion 965 16004 1.19E−05 28231790- 28234747-28234813- 28234746  28234812  28235721  OFD1 inclusion 41060 49482 −113753203- 13753367- 13753466- 13753366  13753465  13754226  OFD1inclusion 41060 49482 −1 13753203- 13753367- 13753466- 13753366 13753465  13754596  OFD1 inclusion 41061 49483 −1 13753203- 13753367-13753466- 13753366  13753465  13754226  OFD1 inclusion 41061 49483 −113753203- 13753367- 13753466- 13753366  13753465  13754596  OFD1inclusion 41116 49538 −1 13757034- 13757121- 13757152- 13757120 13757151  13758207  OFD1 inclusion 41120 49542 −1 13757034- 13757121-13757152- 13757120  13757151  13762533  OFD1 inclusion 41120 49542 −113757034- 13757121- 13757152- 13757120  13757151  13758207  OGTinclusion 428572 420006 −1 70757923- 70764417- 70764486- 70764416 70764485  70766060  OGT inclusion 428572 420006 −1 70757923- 70764417-70764486- 70764416  70764485  70767756  ORC6 inclusion 253273 2476991.63E−04 46726458- 46727005- 46727095- 46727004  46727094  46729473 ORC6 inclusion 253273 247699 1.63E−04 46726458- 46727005- 46727095-46727004  46727094  46728850  ORC6 inclusion 253273 247699 1.63E−0446726458- 46727005- 46727095- 46727004  46727094  46729928  OTCinclusion 97286 103178 −1 38260682- 38262871- 38262994- 38262870 38262993  38267994  OTC inclusion 97301 103193 −1 38262994- 38267995-38268049- 38267994  38268048  38268128  OTC inclusion 97091 102983 −138268279- 38271115- 38271253- 38271114  38271252  38280275  OTOGLinclusion 39780 48379 5.82E−06 80733045- 80735728- 80735943- 80735727 80735942  80746074  PAFAH1B1 inclusion 159550 169377 −1 2576052-2577354- 2577583- 2577353  2577582  2579798  PAFAH1B1 inclusion 159550169377 −1 2576052- 2577354- 2577583- 2577353  2577582  2583457  PAHinclusion 102892 108628 3.98E−06 103240730- 103245465- 103245535-103245464  103245534  103246592  PARN inclusion 190291 178830 4.38E−0514700384- 14702138- 14702177- 14702137  14702176  14702914  PARNinclusion 190291 178830 4.38E−05 14698084- 14702138- 14702177- 14702137 14702176  14702914  PDCD10 inclusion 468332 452270 −1 167402178-167405022- 167405105- 167405021  167405104  167405402  PIGN inclusion101048 106813 8.03E−05 59807713- 59810539- 59810580- 59810538  59810579 59813141  PIGN inclusion 264636 259229 1.77E−05 59777207- 59780367-59780550- 59780366  59780549  59781793  PMS2 inclusion 237932 2401333.98E−06 6031689- 6035165- 6035265- 6035164  6035264  6036956  PMS2inclusion 192316 190109 −1 6022623- 6026390- 6027252- 6026389  6027251 6029430  POLG inclusion 587863 580246 3.98E−05 89862331- 89862459-89862582- 89862458  89862581  89863996  POMGNT1 inclusion 3988 190273.98E−06 46655662- 46656145- 46656190- 46656144  46656189  46656391 PPT1 inclusion 56191 70830 −1 40555185- 40557001- 40557072- 40557000 40557071  40557716  PPT1 inclusion 56191 70830 −1 40555255- 40557001-40557072- 40557000  40557071  40557716  PRMT7 inclusion 266022 2608451.44E−05 68345003- 68349800- 68349978- 68349799  68349977  68355328 PRMT7 inclusion 266022 260845 1.44E−05 68345150- 68349800- 68349978-68349799  68349977  68355328  PRMT7 inclusion 266022 260845 1.44E−0568349553- 68349828- 68349978- 68349827  68349977  68355328  PRMT7inclusion 266022 260845 1.44E−05 68345003- 68349800- 68349978- 68349799 68349977  68358585  PTEN inclusion 280031 264490 4.02E−06 89693009-89711875- 89712017- 89711874  89712016  89717609  PTEN inclusion 427622416983 −1 89693009- 89711875- 89712017- 89711874  89712016  89717609 RAD51B inclusion 221910 223600 4.03E−06 68289048- 68290259- 68290345-68290258  68290344  68292180  RAD51B inclusion 221910 223600 4.03E−0668286571- 68290259- 68290345- 68290258  68290344  68292180  RAD51Cinclusion 128201 133658 1.19E−05 56801462- 56809845- 56809906- 56809844 56809905  56811478  RAD51C inclusion 128201 133658 1.19E−05 56798174-56809845- 56809906- 56809844  56809905  56811478  RAD51C inclusion128201 133658 1.19E−05 56801462- 56809842- 56809906- 56809841  56809905 56811478  RB1 inclusion 428730 420512 −1 48881543- 48916735- 48916851-48916734  48916850  48919215  RB1 inclusion 527935 528310 −1 49050659-49050837- 49050980- 49050836  49050979  49051490  RB1 inclusion 527935528310 −1 49047527- 49050837- 49050980- 49050836  49050979  49051490 RHAG inclusion 13066 28105 3.99E−06 49573544- 49574561- 49574635-49574560  49574634  49574862  RNF216 inclusion 183356 181427 −1 5692142-5751392- 5751471- 5751391  5751470  5752345  RTTN inclusion 219187217210 7.18E−06 67692085- 67695960- 67696038- 67695959  67696037 67697247  SCN1A inclusion 190009 187855 −1 166905460- 166908229-166908499- 166908228  166908498  166909361  SLC10A7 inclusion 623252612215 8.47E−06 147204418- 147214081- 147214133- 147214080  147214132 147215081  SLC12A1 inclusion 8752 23791 1.42E−05 48541874- 48543812-48543968- 48543811  48543967  48548007  SLC4A11 inclusion 1311 163501.20E−05 3208503- 3208905- 3209075- 3208904  3209074  3209157  SMSinclusion 11623 26662 −1 21990109- 21990625- 21990690- 21990624 21990689  21995178  SPAST inclusion 468575 451183 0.00E+00 32323961-32339707- 32339895- 32339706  32339894  32340770  SPAST inclusion 468575451183 0.00E+00 32314675- 32339707- 32339895- 32339706  32339894 32340770  SPG11 inclusion 41362 49786 7.98E−06 44855500- 44856745-44856897- 44856744  44856896  44858051  SPTA1 inclusion 544819 5352403.19E−05 158585194- 158587327- 158587379- 158587326  158587378 158587828  SPTA1 inclusion 12865 27904 −1 158622444- 158623064-158623216- 158623063  158623215  158624400  SPTA1 inclusion 544822535243 −1 158624539- 158626354- 158626447- 158626353  158626446 158627266  SPTB inclusion 544811 535260 −1 65268119- 65268472- 65268553-65268471  65268552  65268943  SRD5A2 inclusion 3341 18380 4.88E−0531754528- 31756441- 31756543- 31756440  31756542  31758672  STXBP1inclusion 520996 511787 −1 130434396- 130435460- 130435541- 130435459 130435540  130438082  SYNGAP1 inclusion 375528 362330 −1 33400030-33400462- 33400584- 33400461  33400583  33402928  TGFBR2 inclusion 1250427543 −1 30715739- 30729876- 30730004- 30729875  30730003  30732911 TJP2 inclusion 397505 384407 7.96E−06 71840324- 71840938- 71841092-71840937  71841091  71842680  TMEM138 inclusion 31190 40147 −1 61133689-61135395- 61135471- 61135394  61135470  61135723  TMEM138 inclusion31190 40147 −1 61133689- 61135395- 61135471- 61135394  61135470 61136068  TMPRSS6 inclusion 30802 39759 1.59E−05 37467073- 37469572-37469686- 37469571  37469685  37470649  TP53 inclusion 80709 916003.98E−06 7577609- 7578177- 7578290- 7578176  7578289  7578370  TP53inclusion 428868 420639 −1 7574034- 7576853- 7576927- 7576852  7576926 7577018  TP53 inclusion 428868 420639 −1 7576658- 7576853- 7576927-7576852  7576926  7577018  TP53 inclusion 428868 420639 −1 7576585-7576853- 7576927- 7576852  7576926  7577018  TP53 inclusion 428868420639 −1 7569563- 7576853- 7576927- 7576852  7576926  7577018  TPOinclusion 4045 19084 3.18E−05 1488627- 1491593- 1491764- 1491592 1491763  1497573  TRAPPC2 inclusion 11512 26551 0.00E+00 13734798-13737990- 13738102- 13737989  13738101  13752162  TRAPPC2 inclusion11512 26551 0.00E+00 13734798- 13737990- 13738102- 13737989  13738101 13752643  TRAPPC2 inclusion 11512 26551 0.00E+00 13734798- 13737990-13738102- 13737989  13738101  13738546  TRAPPC2 inclusion 11512 265510.00E+00 13734798- 13737990- 13738102- 13737989  13738101  13752168 TRIM37 inclusion 5246 20285 8.62E−06 57140010- 57141716- 57141767-57141715  57141766  57148183  TYR inclusion 99582 105471 3.99E−0688911941- 88924370- 88924587- 88924369  88924586  88960990  TYRinclusion 99582 105471 3.99E−06 88911941- 88924370- 88924587- 88924369 88924586  88933430  UROD inclusion 72 15111 3.98E−06 45480509- 45480612-45480679- 45480611  45480678  45481008  VMA21 inclusion 208798 205359 −1150565530- 150572103- 150572213- 150572102  150572212  150573387  VMA21inclusion 208799 205360 −1 150565530- 150572103- 150572213- 150572102 150572212  150573387  VMA21 inclusion 208806 205367 −1 150565120-150572103- 150572213- 150572102  150572212  150573387  VMA21 inclusion208806 205367 −1 150565530- 150572103- 150572213- 150572102  150572212 150573387  VMA21 inclusion 208720 205332 −1 150565120- 150572103-150572213- 150572102  150572212  150573387  VMA21 inclusion 208720205332 −1 150565530- 150572103- 150572213- 150572102  150572212 150573387  VPS13B inclusion 68084 78975 −1 100147366- 100147824-100147962- 100147823  100147961  100148892  WDR35 inclusion 617905609306 −1 20151246- 20153595- 20153740- 20153594  20153739  20166484 WDR35 inclusion 617905 609306 −1 20151246- 20153595- 20153740- 20153594 20153739  20160314  WDR73 inclusion 208470 204991 4.01E−06 85191186-85191768- 85191857- 85191767  85191856  85195944  XPC inclusion 26015299 −1 14208754- 14209757- 14209881- 14209756  14209880  14211937 BRCA1 exclusion 55387 70054 3.98E−06 41215391- 41215891- 41215969-41215890  41215968  41234420  BRCA1 exclusion 55387 70054 3.98E−0641215391- 41215891- 41215969- 41215890  41215968  41277198  BRCA1exclusion 55419 70086 −1 41215391- 41215891- 41215969- 41215890 41215968  41234420  BRCA1 exclusion 55419 70086 −1 41215391- 41215891-41215969- 41215890  41215968  41277198  BRIP1 exclusion 578521 5714013.98E−06 59876661- 59878614- 59878836- 59878613  59878835  59885827 BRIP1 exclusion 491400 485084 −1 59876661- 59878614- 59878836- 59878613 59878835  59885827  CDAN1 exclusion 3182 18221 −1 43026545- 43027298-43027377- 43027297  43027376  43027458  CLN3 exclusion 56290 709292.47E−05 28488957- 28493798- 28493867- 28493797  28493866  28493946 COL6A1 exclusion 17169 32208 3.99E−06 47418086- 47418312- 47418348-47418311  47418347  47418810  COL7A1 exclusion 17437 32476 −1 48619947-48620042- 48620087- 48620041  48620086  48620445  CTSK exclusion 842423463 −1 150778493- 150778578- 150778701- 150778577  150778700 150779161  EBP exclusion 158530 170113 −1 48380296- 48382311- 48382461-48382310  48382460  48385376  ERCC6 exclusion 1700 16739 −1 50701299-50708584- 50708743- 50708583  50708742  50713929  F8 exclusion 1030325342 −1 154129718- 154130326- 154130443- 154130325  154130442 154132180  FBN1 exclusion 547347 538033 3.98E−06 48707965- 48712884-48713004- 48712883  48713003  48713754  FBN1 exclusion 36119 44783 −148707965- 48712884- 48713004- 48712883  48713003  48713754  FIG4exclusion 447336 440905 2.48E−05 110113868- 110117968- 110118055-110117967  110118054  110146290  FLT3 exclusion 16271 31310 4.01E−0628589839- 28592604- 28592727- 28592603  28592726  28597486  GLAexclusion 10768 25807 4.53E−05 100653935- 100654732- 100654789-100654731  100654788  100655653  HFE exclusion 407073 395090 −126091333- 26092955- 26093189- 26092954  26093188  26093346  HFEexclusion 407073 395090 −1 26091333- 26092913- 26093189- 26092912 26093188  26093346  LHCGR exclusion 492757 485710 0.00E+00 48950836-48952815- 48952890- 48952814  48952889  48958365  LHCGR exclusion 492757485710 0.00E+00 48950836- 48952815- 48952890- 48952814  48952889 48956291  MAPT exclusion 14253 29292 2.62E−05 44074031- 44087676-44087769- 44087675  44087768  44091608  MAPT exclusion 98218 1041105.64E−06 44074031- 44087676- 44087769- 44087675  44087768  44091608 MAPT exclusion 14254 29293 −1 44074031- 44087676- 44087769- 44087675 44087768  44091608  OTC exclusion 97139 103031 −1 38226683- 38229049-38229094- 38229048  38229093  38240612  SCN5A exclusion 448976 442549 −138662463- 38663891- 38663981- 38663890  38663980  3867180 1 SDCCAG8exclusion 212141 206783 −1 243449700- 243456393- 243456522- 243456392 243456521  243468014  SDCCAG8 exclusion 212141 206783 −1 243449700-243456393- 243456522- 243456392  243456521  243456700  SDHD exclusion6903 21942 −1 111957684- 111958581- 111958698- 111958580  111958697 111959590  SDHD exclusion 6903 21942 −1 111957684- 111958581- 111958698-111958580  111958697  111959590  SDHD exclusion 6903 21942 −1 111957684-111958581- 111958698- 111958580  111958697  111965528  SNX10 exclusion139565 143196 2.39E−05 26386087- 26400595- 26400682- 26400594  26400681 26404154  SNX10 exclusion 139565 143196 2.39E−05 26396748- 26400595-26400682- 26400594  26400681  26404154  SNX10 exclusion 139565 1431962.39E−05 26393805- 26400595- 26400682- 26400594  26400681  2640415 4STK11 exclusion 216070 213437 −1 1219413- 1220372- 1220717- 1220371 1220716  1221211  TCIRG1 exclusion 5462 20501 4.03E−05 67806587-67808735- 67808814- 67808734  67808813  67809219  TECTA exclusion 228404230005 1.99E−05 121038927- 121039386- 121039635- 121039385  121039634 121058540  TFR2 exclusion 21379 34231 −1 100229569- 100229705-100229822- 100229704  100229821  100230623  TP53 exclusion 428868 420639−1 7574034- 7576525- 7576585- 7576524  7576584  7576852 

Table 19 lists those ClinVar pathogenic mutations predicted to berescued by Compound (I) treatment selected based on top populationalallele frequencies in gnomAD v2.1.1, as described herein, that may bemodulated by Compound (I) toward either or both exon inclusion and exonexclusion.

TABLE 19 ATM, BRCA1, CA5A, DGUOK, DNAH9, GLA, GPX4, GYPA, HBB, IL36RN,KDSR, LIPA, MYO7A, NPHP1, NSD1, ORC6, PARN, PIGN, POLG, SLC12A1, SPTA1,SRD5A2, TCIRG1, and TPO.

One aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ IDNO: 2), CACTAGgtgaga (SEQ ID NO: 3), and CCAgtgagga (SEQ ID NO: 4), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 19.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ IDNO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga (SEQ ID NO: 8), andwherein the wildtype gene transcript is transcribed from a gene selectedfrom Table 19.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ IDNO: 10), CACTAGgtgagc (SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12),AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt(SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO: 16), and wherein the mutantgene transcript is transcribed from a gene selected from Table 19.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence selected fromthe group consisting of: CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ IDNO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20),AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu(SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24), and wherein the mutantgene transcript is transcribed from a gene selected from Table 19.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a predicted wildtype or mutant gene transcript in a cell,wherein the method comprises, contacting the cell with Compound (I),wherein the predicted wildtype or mutant gene transcript includes anucleotide sequence selected from the group consisting of: CTTAG (SEQ IDNO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO:28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO:31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO:34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO:37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO:40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO:43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO:46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO:49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO:52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO:55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO:58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO:61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), wherein Nrepresents any DNA nucleotide, and wherein the predicted wildtype ormutant gene transcript is transcribed from a gene selected from Table19.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT(SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC(SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT(SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG(SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA(SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA(SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC(SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN(SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN(SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), andwherein N represents any DNA nucleotide.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA(SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA(SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU(SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA(SEQ ID NO: 76), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN(SEQ ID NO: 80), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU(SEQ ID NO: 84), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA(SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU(SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN(SEQ ID NO: 98), NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN(SEQ ID NO: 101), and CUGUA (SEQ ID NO: 102), and wherein N representsany RNA nucleotide.

Another aspect described herein is Compound (I) for use in the method,wherein the gene transcript is a predicted wildtype or mutant genetranscript in a cell comprising, a nucleotide sequence selected from thegroup consisting of: NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU(SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC(SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU(SEQ ID NO: 74), AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU(SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG(SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG(SEQ ID NO: 90), UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN(SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU(SEQ ID NO: 100), and CUGUA (SEQ ID NO: 102), and wherein N representsany RNA nucleotide.

One aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 19.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a wildtype gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the wildtypegene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 19.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of: CAAgtaagc (SEQ ID NO:9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11),CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt(SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO:16), and wherein the mutant gene transcript is transcribed from a geneselected from Table 19.

Another aspect described herein is Compound (I) for use in the method,wherein Compound (I) modulates the production of one or more mature RNAisoforms from a mutant gene transcript in a cell, wherein the methodcomprises, contacting the cell with Compound (I), wherein the mutantgene transcript comprises, three exons and two introns operably linkedin the following order: Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3,wherein a 5′ splice site of Exon 2 comprises, a sequence other than asequence selected from the group consisting of: CAAguaagc (SEQ ID NO:17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19),CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu(SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO:24), and wherein the mutant gene transcript is transcribed from a geneselected from Table 19.

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagt (SEQ ID NO:1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO: 3), andCCAgtgagga (SEQ ID NO: 4), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 19.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagu (SEQ ID NO:5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), andCCAgugagga (SEQ ID NO: 8), and wherein the wildtype gene transcript istranscribed from a gene selected from Table 19.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAgtaagc (SEQ ID NO:9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc (SEQ ID NO: 11),CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO: 13), ATCCAAgtatgt(SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), and AGTgtaagta (SEQ ID NO:16), and wherein the mutant gene transcript is transcribed from a geneselected from Table 19.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence selected from the group consisting of: CAAguaagc (SEQ ID NO:17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19),CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu(SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO:24), and wherein the mutant gene transcript is transcribed from a geneselected from Table 19.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CTTAG (SEQ ID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27),CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30),TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33),TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36),TCTCA (SEQ ID NO: 37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39),GAGAG (SEQ ID NO: 40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42),AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51),TTCCC (SEQ ID NO: 52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54),GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57),CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60),AACCT (SEQ ID NO: 61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63),wherein N represents any DNA nucleotide, and wherein the predictedwildtype or mutant gene transcript is transcribed from a gene selectedfrom Table 19.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ ID NO: 28),TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO: 31), TGAGC (SEQ ID NO: 32),CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO: 34), TTTTT (SEQ ID NO: 35),AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO: 40),AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO: 43), GATTA (SEQ ID NO: 44),NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48),TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO: 52),TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO: 55), NTGNN (SEQ ID NO: 56),NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO: 58), NTGTN (SEQ ID NO: 59),AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO: 63), wherein N representsany DNA nucleotide, and wherein the predicted wildtype or mutant genetranscript is transcribed from a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:CUUAG (SEQ ID NO: 64), NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66),CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70),UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73),UUUUU (SEQ ID NO: 74), AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80),AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93),NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98),NUCCU (SEQ ID NO: 99), AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 8.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a predicted wildtypeor mutant gene transcript in a cell comprising, contacting the cell withCompound (I), wherein the predicted wildtype or mutant gene transcriptincludes a nucleotide sequence selected from the group consisting of:NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AAGCU (SEQ ID NO: 77), GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86),ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90),UUCCC (SEQ ID NO: 91), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100),and CUGUA (SEQ ID NO: 102), wherein N represents any RNA nucleotide, andwherein the predicted wildtype or mutant gene transcript is transcribedfrom a gene selected from Table 8.

One aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAgtaagt (SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQID NO: 3), and CCAgtgagga (SEQ ID NO: 4), and wherein the wildtype genetranscript is transcribed from a gene selected from Table 19.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a wildtype genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the wildtype gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAguaagu (SEQ ID NO: 5), GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQID NO: 7), and CCAgugagga (SEQ ID NO: 8), and wherein the wildtype genetranscript is transcribed from a gene selected from Table 19.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc(SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO:13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16), and wherein the mutant gene transcript istranscribed from a gene selected from Table 19.

Another aspect described herein is use of Compound (I) to modulate theproduction of one or more mature RNA isoforms from a mutant genetranscript in a cell comprising, contacting the cell with Compound (I),wherein the mutant gene transcript comprises, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, wherein a 5′ splice site of Exon 2 comprises, asequence other than a sequence selected from the group consisting of:CAAguaagc (SEQ ID NO: 17), GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc(SEQ ID NO: 19), CCAguuagga (SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO:21), AUCCAAguaugu (SEQ ID NO: 22), CUGAAgucagu (SEQ ID NO: 23), andAGUguaagua (SEQ ID NO: 24), and wherein the mutant gene transcript istranscribed from a gene selected from Table 19.

Identification of Potential Therapeutic Targets of Compound (I)

About 20% of all CV-pMUTs were predicted to alter splicing within 50nucleotides of the mutation, and that about 80% of these disruptEnsembl-annotated (GRCh37 version 75) splice sites (FIG. 4A). Theresponsive genes (Gene) containing the top 20 most frequent mutations(gnomAD v2.1.1) (Mutation) are shown in Table 20. The human diseasesassociated with the Mutations are shown in Table 14.

Table 20 lists ClinVar pathogenic mutations (ClinVar) predicted bySplice AI (Prediction) to be rescued by either Gain or Loss afterCompound (I) treatment, with corresponding isoform change (Response)were selected based on top populational allele frequencies in gnomAD(v2.1.1) (Frequency).

TABLE 20 ClinVar Pathogenic Mutations SpliceAI Gene Mutation FrequencyClinVar Prediction Response ATM c.2250G > A 4.39E−05 Synonymous LossInclusion CA5A c.555G > A 1.67E−04 Synonymous Loss Inclusion DGUOKc.591G > A 1.27E−04 Intronic/ Loss Inclusion Synonymous DNAH9 c.1970 +3.18E−04 Intronic Loss Inclusion 4A > G GLA c.639 + 4.53E−05 IntronicGain Exclusion 919G > A GPX4 c.476 + 3.65E−05 Intronic Loss Inclusion5G > A GYPA c.232G > A 3.60E−05 Missense Loss Inclusion HBB c.92G > A1.03E−04 Missense Loss Inclusion IL36RN c.115 + 1.00E−03 Intronic LossInclusion 6T > C KDSR c.879G > A 6.37E−05 Synonymous Loss Inclusion LIPAc.894G > A 8.28E−04 Synonymous Loss Inclusion MYO7A c.2904G > A 3.20E−05Synonymous Loss Inclusion NPHP1 c.1027G > A 6.37E−05 Missense LossInclusion NSD1 c.6152 − 5.96E−05 Intronic Loss Inclusion 5T > G ORC6c.449 + 1.63E−04 Intronic Loss Inclusion 5G > A PARN c.659 + 4.63E−05Intronic Loss Inclusion 4_659 + 7delAGTA PIGN c.963G > A 8.31E−05Synonymous Loss Inclusion POLG c.3104 + 3.98E−05 Intronic Loss Inclusion3A > T SLC12A1 c.1942G > A 6.37E−05 Missense Loss Inclusion SRD5A2c.547G > A 1.59E−04 Missense Loss Inclusion

Minigene Validation of the CNN Model

To validate whether the CNN model correctly predicted mutated exontriplet response to Compound (I) using the minigene system and RT-PCR,the following rules were used to select suitable exon triplets: 1) Exontriplet total length, including introns, was less than 1.5 kb andsuitable for cloning, 2) Exon triplet splicing changes were detectablein fibroblast RNASeq against Compound (I), where the response classescould be used as quality checks of minigene expression; and 3) Wild-typeexon triplet splicing of the minigene recapitulated the responseobserved in the fibroblast RNASeq before and after treatment withCompound (I), thus confirming the splicing process in the minigene wasintact.

Minigene splicing assays for certain genes having exon tripletsharboring mutations were used to confirm the predictive accuracy of theCNN model results. The genes were chosen based on their genomic tripletlength which enabled them to be cloned into a splice vector. Minigenesfor CPSF7, SETD5 and PARP6 were developed (as shown in FIGS. 3E-3G,respectively) with alternatively spliced triplets that the CNN model hadpredicted would respond in the presence of Compound (I). One nucleotidein the 5′ splice site (in adjacent nucleotides from the +2 to +6position) was randomly mutated for each minigene, resulting in mutationsin the +3 position (CPSF7 and PARP6) and the +6 position (SETD5), thenthe response to treatment in both wild-type and mutant constructs waspredicted by the CNN model and subsequently confirmed by RT-PCR. Forexample, FIG. 3E illustrates that the mutated CPSF7 minigene waspredicted to be affected by the presence of Compound (I) towardinclusion and subsequently confirmed by RT-PCR. FIG. 3F indicates thatthe mutated SETD5 minigene was predicted to be affected by the presenceof Compound (I) toward exclusion, which was subsequently confirmed byRT-PCR. FIG. 3G shows that the mutated PARP6 gene isolated from patientcells was predicted to be affected by the presence of Compound (I)toward inclusion, which was also subsequently confirmed by RT-PCR.

Results of Minigene Validation of CNN Model

In one example from Table 18, the IL36RN gene harbors the mutationc.115+6T>C, which is 6 nucleotides downstream of exon 3 and wasannotated as an intronic mutation in a patient with psoriasis (ClinVarID: 40005). SpliceAI predicted that this mutation would cause skippingof Exon 3 and the CNN model predicted that the mutated sequence would beresponsive to Compound (I) treatment, promoting exon 3 inclusion.

Similarly, in another example from Table 18, the c.894G>A mutationlocated at the last nucleotide of exon 8 in LIPA was annotated as asynonymous mutation (ClinVar ID: 203361), leading to deficient activityof lysosomal acid lipase (LAL)^(56,57,59,60) and characterized by theaccumulation of harmful amounts of lipids in cells and tissuesthroughout the body. Mutations in LIPA are expressed in two majorphenotypes: the severe infantile-onset Wolman disease and the milderlate-onset cholesterol ester storage disease (CESD)⁵⁸⁻⁶⁰. The severityof the condition depends on the residual LAL activity⁵⁷. The c.894G>ALIPA gene mutation is the most common mutation in the LIPA gene, foundin about 50% of individuals with LAL deficiency⁵⁸. This mutation isresponsible for the milder disease CESD and leads to skipping of exon 8.SpliceAI predicted the mutation would cause exon 8 skipping while theCNN model predicted the mutated sequence would be responsive to Compound(I) treatment, promoting exon 8 inclusion (see FIG. 4C). To confirm theprediction for LIPA, a cell line (Coriell Cell Repository) carrying thec.894G>A mutation in the LIPA gene was treated with Compound (I) (60 μM)for 24 hours. As predicted and shown in FIG. 4C, the WT sequence wasunaffected, but Compound (I) promoted the inclusion of exon 8 for themutated gene, with cells showing a significant 10% increase in normaltranscript levels.

In another example from Table 18, the ClinVar and CNN model predictionsrelated to the CFTR gene carrying a c.2988G>A mutation (see FIG. 4D)were confirmed by stably expressing a minigene containing the fulllength CFTR coding sequence carrying the c.2988G>A mutation and flankingintrons (EMG-MUT)⁶³ in HEK293 cells. The c.2988G>A mutation was reportedto cause skipping of exon 18 in the CFTR gene and is associated withabnormal CFTR function and a mild form of Cystic Fibrosis⁶⁴. The CNNmodel predicted that CFTR exon skipping would be rescued by Compound (I)treatment (as shown in FIG. 4D)⁵⁹. Using RT-PCR, the minigene wasconfirmed to harbor the mutation (EMG-MUT), showing only 5% exon 18inclusion. As shown in FIG. 4D, treatment with Compound (I) (60 μM) for24 hours significantly increased exon inclusion in the EMG-MUT.

In another example from Table 18, a minigene encompassing MLH1 exons 16to 18 and flanking exon 17 intronic sequences, with the c.1989 G>Amutation was prepared. This mutation was predicted by SpliceA1 to causeskipping of exon 17 in the MLH1 gene. The CNN model predicted that theskipping of this exon would be rescued by Compound (I) treatment. Thec.1989 G>A mutation in MLH1 is associated with hereditary nonpolyposiscolorectal cancer (HNPCC) or Lynch syndrome (MIM #120435). Individualswith MLH1 mutations also have an increased risk of cancers of theendometrium, ovaries, stomach, small intestine, liver, gallbladder duct,upper urinary tract, and brain^(14-16,65). In order to validate thetreatment effect on the splicing of exon 17, transfected cell lines weretreated with Compound (I) (60 μM) for 24 hours. As shown in FIG. 4E, thetreatment significantly promoted exon 17 inclusion.

In another example from Table 18, several MAPT minigenes encompassingexons 9 to 11 and flanking exon 10 intronic sequences, with the threemutations listed in Table 17: c.1866+3 G>A, c.1865 G>A or c.1788 T>Gwere prepared. These mutations were predicted by SpliceA1 to promoteinclusion of MAPT exon 10. The CNN model predicted that Compound (I)would promote exon 10 exclusion. An increase in MAPT exon 10 inclusionis responsible for familial frontotemporal dementia and Parkinsonismlinked to chromosome 17 (FTDP-17, MIM #600274). Alternative splicing ofMAPT exon 10 is tightly regulated and generates two tau isoforms withthree (3R tau, exon 10 skipped) or four (4R tau, exon 10 included)microtubule-binding repeats, the latter having an increased affinity formicrotubules. Exon 10 is expressed only in adult human brain and 3R and4R tau isoforms are expressed in approximately equal amounts. Mutationsaffecting exon 10 splicing result in an up to 6-fold excess of 4R tauand in an elevated 4R/3R ratio⁶⁸⁻⁷². Elevated 4R/3R ratio leads tosaturation of microtubule binding sites and increase of unbound 4R tauwhich assembles into filaments. The most common mutation in MAPT gene isthe C to T substitution in intron 10, c.1866+16C>T, commonly referred toas IVS10+16. This mutation increases inclusion of exon 10. The MAPTc.1866+16C>T mutation was not initially identified by SpliceAI to affectsplicing, but the CNN model for this mutation predicted the treatmenteffect of Compound (I) on exon 10 splicing to promote exon 10 exclusion.The MAPT minigene carrying the c.1866+16C>T mutation was used tovalidate the CNN Model prediction. The use of Compound (I) treatment toaffect splicing of MAPT exon 10 was validated in transfected cell linestreated with Compound (I) (60 μM) for 24 hours. As shown in FIG. 4F, thetreatment significantly promoted exon 10 exclusion for all threemutations tested.

ELP1 Gene Modulation Using Kinetin

Splicing alterations identified at three 5′ splice site junctions intriplets of consecutive exons in the Elongator complex Protein 1 gene(ELP1), having a 5′ splice site mutation resulting in Exon 20 exclusion,after treatment with kinetin, a small molecule 6-furfurylaminopurinesplicing modulator compound, have demonstrated correctivesplicing^(44,46-50,93) A Percent Spliced In (PSI) change of 0.57 wasassessed by RNA sequencing for ELP1 exon 20 splicing after kinetintreatment^(44,46-50,93). 42 additional exon-usage differences inresponse to kinetin were observed: 11 of the usage differences promotedinclusion of the middle exon and 31 usage differences induced skippingof the middle exon^(44,46-50,93).

Kinetin is a naturally occurring small molecule splicing modulatorcompound with a safe absorption, distribution, metabolism, and excretion(ADME) profile; however, extremely high doses are necessary to achieveinclusion of Exon 20 in vivo^(44,46-50,93). As described herein, invitro and in vivo splicing assays in various cell lines, includingpatient cells, have identified Compound (I) as a potent and efficacioussmall molecule splicing modulator compound.

ELP1 Gene Modulation Using Compound (I)

Compound (I) was evaluated in vivo to determine whether splicingcorrection can lead to a concomitant increase in ELP1 protein. In brief,TgFD9 transgenic mice, which carry the human ELP1 gene with a Exon 20splice mutation, were treated by oral gavage once daily for 7 days withCompound (I) as a suspension in 0.5% HPMC, 0.1% Tween 80 at a dose of10, 30, 60 or 100 mg/kg. The mice used for this study were housed in ananimal facility, provided with access to food and water ad libitum, andmaintained on a 12-hour light/dark cycle. For routine genotyping,genomic DNA was prepared from tail biopsies and PCR was carried out todetect the TgFD9 transgene using the following primers—forward5′-GCCATTGTACTGTTTGCGACT-3′; reverse, 5′-TGAGTGTCACGATTCTTTCTGC-3′. Micewere sacrificed 1 hour after the last dose.

Brain, liver, lung, kidney, heart and skin tissues were removed and snapfrozen in liquid nitrogen. Tissues were homogenized in ice-cold QIAzolLysis Reagent (Qiagen), using Qiagen TissueLyser II (Qiagen). Total RNAwas extracted using the QIAzol reagent procedure. The yield, purity andquality of the total RNA for each sample were determined using aNanodrop ND-1000 spectrophotometer. Full-length and mutant ELP1 mRNAexpression was quantified by quantitative real-time PCR (qRT-PCR)analysis using CFX384 Touch Real-Time PCR Detection System (BioRad).Reverse transcription and qPCR were carried out using One Step RT-qPCR(BioRad). The mRNA levels of full-length ELP1, mutant Δ20 ELP1 and GAPDHwere quantified using Taqman-based RT-qPCR with a cDNA equivalent of 25ng of starting RNA in a 20-μl reaction. To amplify the full-length ELP1isoform, FL ELP1 forward primer 5′-GAGCCCTGGTTTTAGCTCAG-3′; reverseprimer 5′-CATGCATTCAAATGCCTCTTT-3′, and FL ELP1 probe5′-TCGGAAGTGGTTGGACAAACTTATGTTT-3′ were used. To amplify the mutant(Δ20) ELP1 spliced isoforms, Δ20 ELP1 forward primer,5′-CACAAAGCTTGTATTACAGACT-3′; reverse primer 5′-GAAGGTTTCCACATTTCCAAG-3′ and Δ20 ELP1 probe 5′-CTCAATCTGATTTATGATCATAACCCTAAGGTG-3′ wereused. The ELP1 forward and reverse primers were each used at a finalconcentration of 0.4 μM. The ELP1 probes were used at a finalconcentration of 0.15 μM. Mouse GAPDH mRNA was amplified using 20× geneexpression PCR assay (Life Technologies, Inc.). RT-qPCR was carried outat the following temperatures for indicated times: Step 1: 48° C. (15min); Step 2: 95° C. (15 min); Step 3: 95° C. (15 sec); Step 4: 60° C.(1 min); Steps 3 and 4 were repeated for 39 cycles. The Ct values foreach mRNA were converted to mRNA abundance using actual PCRefficiencies. ELP1 FL and Δ20 mRNAs were normalized to GAPDH and vehiclecontrols and plotted as fold change compared to vehicle treatment. Datawere analyzed using SDS software.

Compound (I) In Vivo ELP1 Protein Quantification

Tissue samples were collected, snap frozen in liquid nitrogen, weighed,and homogenized on the TissueLyzer II (Qiagen) in RIPA buffer (Tris-HCl50 mM, pH 7.4; NaCl 150 mM; NP-40 1%; sodium deoxycholate 0.5%; SDS0.1%) containing a cocktail of protease inhibitors (Roche) at a tissueweight to RIPA buffer volume of 50 mg/mL. The samples were thencentrifuged for 20 min at 14,000×g in a microcentrifuge. The homogenateswere transferred to a 96-well plate and diluted in RIPA buffer to ˜1mg/mL for ELP1-HTRF and ˜0.5 mg/mL for total protein measurement usingthe BCA protein assay (Pierce). Samples were run in duplicate andaveraged. For the ELP1-HTRF assay, 35 μL of tissue homogenate weretransferred to a 384-well plate containing 5 μL of the antibody solution(1:50 dilution of anti-ELP1 D2 and anti-ELP1 cryptate from Cisbio). Theplate was incubated overnight at room temperature. Fluorescence wasmeasured at 665 nm and 620 nm on an EnVision multilabel plate reader(Perkin Elmer). Total protein content was quantified in each tissuehomogenate using the BCA assay. The total protein normalized change inELP1 protein signal for Compound (I) and vehicle treated tissue samplewas calculated as ratio of the signal in the presence of the testcompound (e.g., Compound (I)) over the signal in the absence of theCompound (I) (vehicle control).

Treatment increased full-length ELP1 transcript in a dose-dependentmanner and led to at least a two-fold increase in functional ELP1protein in brain, liver, kidney, heart and skin (FIGS. 7A-7E). Thetreatment was found to be well tolerated with no weight loss or adverseeffects observed in the treated groups. The level of splicing correctioncorrelated with Compound (I) tissue distribution (FIGS. 7F-7G). Theseresults demonstrated that treatment with Compound (I), which correctssplicing of the ELP1 transcript, significantly increased the level offunctional protein in vivo in all tissues, including the brain (FIGS.7A-7B).

Materials and Methods HEL-293 Cell Culture

HEK-293T (ATCC) cells were cultured in Dulbecco's modified Eagle'smedium (11995-065, D-MEM, Gibco) supplemented with 10% fetal bovineserum (FBS, 12306C, SIGMA) and 1% penicillin/streptomycin (30-009-CI,Corning).

Minigene Generation and Site Direct Mutagenesis

Wild-type and mutant double-stranded DNA (dsDNA) fragments, selectedbased on low nucleotide length and exon-skipping probability, wereordered through GENEWIZ (FragmentGENE). Adenosine was enzymaticallyattached to DNA fragment 3′ ends with Taq Polymerase in the presence of200 nM dATP and 2 mM MgCl₂ at 70° C. for 30 min. Fragments were ligatedinto linearized pcDNA™3.1/V5-His TOPO® TA plasmid (K480001 ThermoFisherScientific) according to manufacturer's instructions. After colonyselection and sequence confirmation, each plasmid was finally purifiedusing MIDIprep kit (740410, NucleoBond® Xtra Midi, Takara, MountainView, Calif.). Concentrations were determined using a nanodropspectrometer.

Wild-Type and Mutant CFTR Minigene

HEK-293 cells stably transfected with the expression minigenes (EMGs)for the full-length coding sequence and flanking intron sequence of theCystic Fibrosis Transmembrane Conductance Regulator (CFTR) (courtesy ofDr. Garry R. Cutting, Johns Hopkins University school of Medicine,Baltimore, Md.) were cultured in D-MEM supplemented with 10% FBS (FBS),1% penicillin/streptomycin and 0.1 mg/mL Hygromycin (SIGMA).

Wild-Type and Mutant ELP1 and LIPA Culture in Patient Cells

Patient human fibroblast cells GM04663 (Coriell Cell Repository)carrying the c.2204+6T>C mutation in ELP1 and patient human fibroblastcells GM03111 (Coriell Cell Repository) carrying the c.894G>A mutationin LIPA and human wild type fibroblasts (Coriell Cell Repository) wereused for the RNA sequence and were cultured in D-MEM supplemented with10% FBS and 1% penicillin/streptomycin.

HEK293 Transfection

HEK293T cells were seeded in 6-well culture plates at 1.20×10⁶cells/well in D-MEM, 10% FBS, without antibiotics and incubatedovernight to reach approximately 90% confluence. Transfection wasperformed with FuGENE® HD Transfection Reagent (E2311, Promega) usingthe FuGENE-DNA ratio at 3.5:1 and following manufacturer protocol. After4 hours of incubation at 37° C., cells were plated at a density of 3×10⁴cells/well in a poly-L-lysine coated 96-well plate for the dualluciferase minigene assay or at the density of 8.5×10⁵ cells/well into6-well plates for minigene transfection. After 16 hours incubation at37° C., Compound (I) or DMSO was added at the desired concentrations asdescribed in the next paragraph and kept in culture for other 24 hours.

Fibroblast Cell Lines

Six different human fibroblast cell lines from healthy individuals wereobtained from Coriell Institute and cultured in D-MEM (Gibco)supplemented with 10% FBS and 1% penicillin/streptomycin. Cells werecounted and plated in order to achieve semi-confluence after eight days.Twenty-four hours after plating, the medium was changed and cells weretreated with Compound (I) or DMSO to a final concentration of 30 μM and0.5%, respectively. DMSO was used as vehicle. The concentration ofCompound (I) was chosen to induce splicing changes and ELP1 proteinincrease. After seven days of treatment, cells were collected, and RNAwas extracted using the QIAzol Reagent following the manufacturer'sinstructions. RNASeq libraries were prepared using the strand-specificdUTP method^(24,90,91).

The six different wildtype (WT) human fibroblast cell lines shown inTable 22 included three wildtype human fibroblast cell lines from threecaucasian males (10, 12, and 32 years of age) and three caucasianfemales (3 month, 11, and 11 years of age).

TABLE 22 Wildtype (WT) Human Fibroblast Cell Lines Coriell # GenotypeSex Age Race AG16409 WT Male 12 years Caucasian GM03348 WT Male 10 yearsCaucasian GM08402 WT Male 32 years Caucasian GM01652 WT Female 11 yearsCaucasian GM02036 WT Female 11 years Caucasian GM00041 WT Female 3months Caucasian

RNA Isolation and RT-PCR Analysis

After treatment, the cells were collected and RNA was extracted withQIAzol Lysis Reagent (79306, Qiagen) following the manufacturer'sinstructions. The yields of the total RNA for each sample weredetermined using a Nanodrop ND-1000 spectrophotometer.

Reverse transcription was performed using 0.5-1 μg of total RNA, RandomPrimers (C1181, Promega), Oligo(dT)15 Primer (SEQ ID NO: 103) (C1101,Promega), and Superscript III reverse transcriptase (18080093,ThermoFisher Scientific) according to the manufacturer's protocol. cDNAwas used to perform PCR reaction in a 20-25 μL volume, using GoTaq®green master mix (MT123, Promega). The primers and melting temperature(Tm) used were according to the manufacturer's protocol. To measureminigene splicing, forward and reverse primers were designed to includethe TOPO/V5 plasmid vector and flanking exon sequence in order to avoidendogenous gene detection. PCR reaction was performed as follows: 32cycles of (95° C. for 30 s, T_(m) for 30 s, 72° C. for 30 s), productswere resolved on a 1.5-3% agarose gel, depending on the dimension of thebands to be separated, and visualized using ethidium bromide staining.

Ratios between isoforms having the middle exon included or excluded wereobtained using the integrated density value (IDV) for each correspondentband, and then assessed using Alpha 2000™ Image Analyzer and quantifiedby ImageJ software. The level of exon inclusion was calculated aspreviously described⁴, where the relative density value of the bandrepresents inclusion and is expressed as a percentage. Validation of thesemi-quantitative RT-PCR method for the measurement of exon inclusionwas performed using RT-qPCR⁴.

RNA Sequencing

Briefly, RNA sample quality (based on RNA Integrity Number, or RIN) andquantity was determined using the Agilent 2200 TapeStation, with between100-1000 ng of total RNA used for library preparation. Each RNA samplewas spiked with 1 μL of diluted (1:100) External RNA Controls Consortium(ERCC) RNA Spike-In Mix (4456740, ThermoFisher Scientific), alternatingbetween mix 1 and mix 2 for each well in the batch. Samples were thenenriched for mRNA using polyA capture, followed by stranded reversetranscription and chemical shearing to make appropriate stranded cDNAinserts. Libraries were finished by adding Y-adapters, with samplespecific barcodes, followed by between 10-15 rounds of PCRamplification. Libraries were evaluated for final concentration and sizedistribution by Agilent 2200 TapeStation and/or qPCR, using LibraryQuantification Kit (KK4854, Kapa Biosystems), and multiplexed by poolingequimolar amounts of each library prior to sequencing. Pooled librarieswere 50 base pair paired-end sequenced on Illumina HiSeq 2500 acrossmultiple lanes. Real time image analysis and base calling were performedon the HiSeq 2500 instrument using the HiSeq Sequencing Control Software(HCS) and FASTQ files demultipled using CASAVA software version 1.8.RNASeq reads were mapped to the human genome Ensembl GRCh37 by STARv2.5.2a allowing 5% mismatch^(24,90,91). The exon triplet index wasbuilt according to transcriptome Ensembl GRCh37 version 75. Readsspliced at each exon triplet splice junction were calculated by STAR onthe fly.

Differential Splicing Analysis

For each exon triplet in a certain biological replicate, the ψ (PercentSplice In) value was calculated as (0.5*(R1+R2)/(0.5*(R1+R2)+R3). Theaverage ψ was calculated for treated and untreated conditions, followedby calculation of ψ change. For a certain exon triplet in a certainbiological replicate, a 2×2 table was created, where the four cells ofthe table represent number of reads supporting middle exon inclusion andskipping before and after treatment. Thus, for each exon triplet, atotal of six 2×2 tables were created for each of the six biologicalreplicates. A Cochran-Mantel-Haenszel test was applied to test whetheran association between treatment and splicing across all replicates(namely whether the cross-replicate odds ratio is 1 or not) could bedetermined. For each exon triplet, a p value for theCochran-Mantel-Haenszel test was reported. Benjamini-Hochbergfalse-discovery-rate (BH FDR) correction was finally applied top valuesof all triplets.

The primers and melting temperature (Tm) that were used for RNAIsolation and RT-PCR Analysis are shown in Table 20A AND 20B.

TABLE 20A Forward Primers SEQ ID Gene Forward 5′-3′ NO Tm ELP1CCTGAGCAGCAATCATGTG 111 58 C° KLC1 CGCAGTGGTTCCTTTAGC 112 60 C° LPIN1GCTGTGATTTACCCTCAGTCAGC 113 64 C° HSD17B4 GCAGAAAGAGGAGCGTTA 114 56 C°SLC4A7 GCTACAGAGGACTGGACG 115 60 C° LRRC28 GATATAGTGCTGCAGCGTGC 11660 C° AFMID GCCTTTCTTCCTGTTCTTTCACG 117 60 C° CD99P1CGACCCAGCACCTCTTAATTC 118 62 C° CRYZ GCACTGCTGGTACTGAGGAAG 119 64 C°IP6K2 AACAAGCCAAGGAGCCAAGA 120 62 C° EVC TGCCCTGAAGCTGATGAAGG 121 62 C°EPB41L2 GGAGAAGTACCTGATGCCGAC 122 60 C° CYLD GATGGTTCTACACAGCCACC 12362 C° MEGF6 CTGGTTTGGAGAGGCCTGTG 124 60 C° MYEF2 GTACCGTGGTGCGATGACTA125 60 C° ASXL1 GCCTCGAGTTGTCCTGACTC 126 60 C° SPTAN1CGATCGTCAGGGTTTTGTGC 127 60 C° COPS8 CTGAGGGACAGTCTGGGGTT 128 60 C°PDZD11 GTCAGTGAGCGGAGTCTGAG 129 60 C° KTN1 AGGCAGAGATGGAACGATCT 13060 C° SPPL2A TCATGGTTGAACTCGCAGCT 131 60 C° LIPA CCCAGAGTGCGTTTTTGAA 13260 C° CFTR GCAGTGATTATCACCAGC 133 58 C° PTEN TTGCACAATATCCTTTTGAAGACCA134 60 C° CPSF7 ATTGCCCTTGACCCAGAGTT 135 60 C° SETD5TGTGGTGGAATTGCCCTTAC 136 60 C° MLH1 GTGGAATTGCCCTTGAGC 137 60 C° PARP6GGAATTGCCCTTGATCATCT 138 60 C° MAPT ACCCAAGTCGCCGTCTTCCGCC 139 60 C°

TABLE 20B Reverse Primers SEQ ID Gene Reverse 5′-3′ NO Tm ELP1TACATGGTCTTCGTGACATC 140 58 C° KLC1 CACTGCTGCTGCTGTCG 141 60 C° LPIN1CTTAGCAGCCTGCGGCAGC 142 64 C° HSD17B4 GTTGGCCACTGCTTTTCC 143 56 C°SLC4A7 CTAGAACTGGACCTGTGCTCC 144 60 C° LRRC28 CAACTATGTTATTTGAGTGCAGG145 60 C° AFMID GGTGAGCACGTTGTCCTTCT 146 60 C° CD99P1CGGTGGAATCAGGCTGCTTG 147 62 C° CRYZ CTTTGCCATGGTGTCTCGTGG 148 64 C°IP6K2 ATTCAGGCCACACTTCCCTG 149 62 C° EVC GGTGCCAGCGTCTGCTTC 150 62 C°EPB41L2 CTCACTCTCACTGCTGCTG 151 60 C° CYLD CTTCCCAGTAGGGTGAAGTGAC 15262 C° MEGF6 GGGACGGACTGCAACCTCA 153 60 C° MYEF2 TCTGACAAATATCTGGTTGCCT154 60 C° ASXL1 TTCAGGCAGGAGGAAGAGGA 155 60 C° SPTAN1TTCTGGAGCACCTCAACCTG 156 60 C° COPS8 ATGGAGCAAATATAAAGCTAGAAGC 157 60 C°PDZD11 TGAGGAGGAATCCATGCTGG 158 60 C° KTN1 TGCAAATCACCAGCTACCTTCT 15960 C° SPPL2A TGAGGCACACACTCATTACTGA 160 60 C° LIPA CCCAGTCAAAGGCTTGAAAC161 60 C° CFTR GGAGGAAATATGCTCTCAAC 162 58 C° PTENTTAGCATCTTGTTCTGTTTGTGGA 163 60 C° CPSF7 GAGCGAATAACCTGGATCAGC 164 60 C°SETD5 GCAGAATTGCCCTTCTGATA 165 60 C° MLH1 CACTGTGCTGGATATCTGCTG 16660 C° PARP6 AATTGCCCTTCTGCAGTTTG 167 60 C° MAPT CACCTTGCTCAGGTCAACTGGT168 60 C°

In Vitro and In Vivo Compound (1) Treatment

Compound (I) (>9900 pure) was mixed in 100% DMSO to yield 40 mM stocksolutions. Working solutions (10×) were prepared by dilution to 500 DMSOin phosphate-buffered saline (PBS, GIBCO). The final DMSO concentrationin the treated or untreated cells was 0.5%. Kinetin was purchased fromSigma (K3253).

Cells to be treated with Compound (I) were seeded at the appropriatedensity in specific vessels to reach semiconfluency at the time oftreatment. BEK293T cells transfected with minigenes were seeded in 6wells and patient fibroblasts were seeded in 10 cm dishes using thedescribed media. The following day, the media was changed with regulargrowth media supplemented with Compound (I) or DMSO working solutions toobtain final concentrations of 60 μM Compound (I) and 0.05% DMSO. Theconcentration of 60 μM for dosing Compound (I) was chosen to maximizethe possible effect on splicing. Cells were collected for RNA extraction24 hours after compound or DMSO addition.

Compound (I) ELP1 Dual-Luciferase Splicing Assay

The Rluc-FD-Fluc plasmid used for the dual-luciferase splicing assay wasderived using the ELP1 FD minigene^(44,45,93) containing the ELP1genomic sequence spanning exon 19-21 inserted into spcDNA3.1/V5-His Topo(Invitrogen). The firefly luciferase (FLuc) coding sequence was insertedimmediately after exon 21 and Renilla luciferase (RLuc) upstream of exon19. Characterization of the assay demonstrated that RLuc was expressedeach time a transcript was generated from the reporter plasmid, whileFLuc was only expressed when exon 20 was included in the transcript,thereby keeping FLuc in-frame. Evaluation of FLuc/RLuc expressionprovided the percent exon inclusion in the splicing assays. To performthe dual-luciferase assay, HEK-293T cells were transfected with theminigene plasmid and treated with Compound (I) for 24 hours as describedabove. After treatment, cells were washed once in PBS and lysed for 25minutes at room temperature using 50 μL/well of passive lysis buffer(E1941, Promega). Luciferase activity was measured in each sample (20μL) using the Dual-Luciferase® Reporter Assay reagents (Promega) and theGloMax® 96 Microplate Luminometer (Promega), following manufacturer'sinstruction, in a 96 well format⁴⁹. The integration time on theluminometer was set at 10-seconds. Compound (I) and kinetin wereserially diluted in DMSO and PBS to generate concentration-responsecurves over eight concentrations, with each point run in quadruplicate.Cells cultured in the presence of 0.5% DMSO were used as controls andrun in each plate in quadruplicate.

Minigene Protein Isolation and Western Blot Analysis

Protein extracts were obtained by homogenizing cells in RIPA buffer(Tris-HCl 50 mM, pH 7.4; NaCl 150 mM; NP-40 1%; sodiumdeoxycholate 0.5%;SDS 0.1%, 1 mM DTT) containing protease and phosphatase inhibitorcocktail (Roche). Insoluble debris were discarded after centrifugationand protein concentration was determined using Pierce® BCA Protein AssayKit (Thermo Scientific). For LIPA WB, 30 μg of protein lysate wasseparated on NuPage 10% Bis-Tris gel (Invitrogen) and transferred intonitrocellulose membrane (Thermo Scientific). Membrane was blocked inOdyssey blocking buffer (Licor biosciences) for 1 h at room temperatureand incubated overnight at 4° C. with a mouse monoclonal antibodyagainst LIPA (Abnova clone 9G7F12, 1:200) and with a rabbit polyclonalantibody against actin (Sigma, 1:5000). Membranes were washed 3 times inPBS with 0.1% tween 20 and incubated with IRDye secondary antibodies(Licor biosciences) for 1 h at room temperature. Protein bands werevisualized by Odyssey CLx imager (Licor biosciences).

Compound (I) Treatment in a LIPA Cell Model

Wolman disease and CESD are both caused by mutations in LIPA. Wolman islethal in infancy, whereas CESD patients have some residual enzymeactivity and therefore have a milder clinical course. Patients with only3% of the normal level of LIPA transcript have the much milder diseaseCESD.

Patient fibroblasts carrying the major LIPA splicing mutation, c.894G>Awere treated with 60 μM of Compound (I) for seven days (FIG. 8A). Thetreatment led to a 10% increase in functional LAL enzyme in mutatedcells (FIG. 8B). Given that a 3% increase in residual LAL enzymeactivity is enough to distinguish Wolman disease, which is lethal ininfancy, from the much milder CESD, a 10% increase in functional LAL canbe predicted to have clinical benefit, and Compound (I) increased exon 8inclusion and lead to a 10% increase in functional protein in a patientcell line, suggesting high potential therapeutic efficacy.

CFTR Minigene Preparation

For CFTR WB, 40 μg of protein lysate was separated on 7.5% Criterion TGXprotein gel (BioRad) and transferred to a PVDF membrane using aTrans-Blot Turbo Transfer System (BioRad). After blocking in 5% non-fatdry milk (BioRad), the membrane was probed with mouse monoclonalanti-CFTR antibody (1:5000 in PBST) that recognizes amino acids1204-1211 (596, CFFT, North Carolina Chapel Hill). Rabbit monoclonalanti-Na+K+ ATPase (Abcam) (1:50,000 in PBST) was used as a loadingcontrol. Secondary antibodies were anti-mouse (1:150,000 GE Healthcare)and anti-rabbit (1:100,000 GE Healthcare), respectively. Blots wereexposed on film using ECL Primer Western Blotting Detection Reagent (GEHealthcare)

Creation of 293-Flp-In and CFBE-Flp-In Stable Cell Lines

WT CFTR-EMG-i14-i18, CFTR-EMG-i14-i18 harboring c.2988G>A, Flp-In-CFBE,and Flp-In-293 cells stably expressing WT-EMG and c.2988G>A EMG weregenerated. Both Flpin-293 and Flp-In-CFBE cells lack endogenous CFTRexpression (CFBE41o-) and contain a single Flp recombinase target site.Co-transfection of EMG plasmid with pOG44 (a plasmid encoding Flprecombinase) allowed for genomic integration at the FRT site. Hygromycinwas used for stable cell selection.

CFTR Functional Assessment

Assessment of CFTR channel function and response to Compound (I) wasperformed in CFBEs stably expressing c.2988G>A. Briefly, CFBE stablecell lines were plated on snapwell filters. When transepithelialresistance reached ˜200Ω (˜ 5-7 days) as measured using Voltammeter(Physiologic Instruments), cells were treated with Compound (I) atvarying doses (0.3 μM to 10 μM) for next 3 days. Filters were mounted inUssing chambers (Physiological Instruments). A high chloride solutionwas added to the basolateral chamber and a low chloride solution wasadded to the apical chamber. After equilibration of currents, 10 μMforskolin (Selleckchem) was added to the basolateral side to activateCFTR channels via cAMP signaling. Currents were allowed to plateau,followed by acute addition of 10 μM ivacaftor at apical side for CFTRpotentiation (Selleckchem). Inhibition of CFTR was performed using 10 μMInh-172 (Selleckchem) added to the apical chamber. FIG. 9C shows a dropin short-current (ΔIsc), defined as the current inhibited by Inh-172after sustained Isc responses were achieved upon stimulation withforskolin alone or sequentially with ivacaftor, was a quantifiablemeasurement assigned to CFTR channel function.

Validation of CFTR as a Therapeutic Target for Compound (I)

To evaluate the efficacy of Compound (I) to correct CFTR aberrantsplicing caused by the c.2988G>A mutation (FIG. 9 ) in a Flp-In-293stable cell line expressing c.2988G>A CFTR-EMG-i14-i18 were generated tocontain full-length introns 14 and 16, and abridged introns 15, 17 and18. The c.2988G>A variant is located in the last nucleotide position ofexon 18 and results in a synonymous change (Gln996Gln) at the proteinlevel. RT-PCR using CFTR specific primers revealed about 3% normalspliced transcript in the Flp-In-293 stable cells expressing 2988G>A(FIG. 9B). Treatment with Compound (I) at 60 μM for 5 days increasedexon 18 inclusion by 10% (FIG. 9B) confirming the CNN model prediction.Further, the results suggested that an optimized form of the SMC can bebeneficial for other forms of FTD caused by gain of function mutationsin exon 10, such as P301L, P301S or the S305N, since treatment couldreduce the level of mutated transcript.

Compound (I) Treatment in a CFTR Cell Model

CFTR protein levels was assessed in Flp-In-293 cells stably expressingthe c.2988G>A splicing variant after treatment with Compound (I) for 5days. FIG. 9A shows that the WT CFTR EMG_il4-i18 control cell lineproduced predominantly the higher molecular weight, complex-glycosylatedmature protein (band C˜170 kDa) as well as some lower molecular weight,core-glycosylated immature protein (band B). Flp-In-293 c.2988G>A stablecells treated with DMSO produce ˜3% of WT complex-glycosylated matureCFTR protein while treatment with 60 μM of Compound (I) for 5 daysincreased the amount of mature CFTR protein to ˜20% of WT (FIG. 9B).

The ability of Compound (I) to rescue chloride channel function was alsoassessed. CF bronchial epithelial (CFBE) cell lines was generated tostably express the splicing mutation c.2988G>A. Cells were grown inmonolayers on filters and treated with increasing doses of Compound (I)(0.3 μM-10 μM) or DMSO for 3 days. Chloride channel function wasassessed by measuring short circuit current (I_(sc)) on treated CFBEcells. Forskolin was added to initiate CFTR channel activity viacAMP-mediated signaling, with further channel activation by Ivacaftorand inhibition with Inh-172, a CFTR-specific inhibitor (FIG. 9C,representative Isc tracing). CFTR-specific change in current(ΔI_(sc)±SD) allows for measurement of chloride channel function (FIG.9C). Residual CFTR channel activity was observed in DMSO treated CFBEstable cells expressing c.2988G>A (ΔI_(sc)=12.3±2.7 μA/cm², FIG. 9C).Significant recovery of CFTR function (˜3 fold) was observed followingtreatment with Compound (I) at 1, 3, 6, and 10 μM for 3 days, with amaximal increase in CFTR function achieved using 3 μM of Compound (I)(ΔI_(sc)=37.168±4.32 μA/cm², FIG. 9C). Importantly, the acute additionof Ivacaftor resulted in ˜2 fold improvement in CFTR function inCompound (I) treated cells. These results showed that Compound (I)treatment alone increased chloride channel function to ˜20% of WT, andto ˜30% of WT in combination with Ivacaftor. Given that slight residualCFTR function can lead to a mild form of CF, the increase in chloridechannel function to 20% of WT by treatment with Compound (I) can be aprediction of clinical significance and indicates that thesplicing-targeted approach of the present disclosure is potentiallyefficacious.

Compound (I) Treatment in an ELP1 Minigene

Compound (I) corrected splicing of ELP1 in a minigene system. In vivosplicing correction of ELP1 in a humanized transgenic mouse model led toan increase of ELP1 protein in all tissues, including the brain (FIGS.7A-7B).

Results

The results demonstrated herein indicate that the identification ofsplicing potential for a SMC can provide druggable targets, where even asmall increase in functional protein may provide a dramatic therapeuticeffect for a neurologic disease phenotype. To determine the potential ofCompound (I) to correct splicing of other genes, the machine learningapproach using sequence signatures to predict targetable splicingdefects was developed as described. The resulting CNN Model identified39 CNN Motifs important for drug response, with 2 sets of 12 and 13 CNNMotifs accounting for most of the Compound (I) sensitivity when the CNNMotif is located close to the 5′ splice site. Evaluation of splice sitestrength in drug responsive triplets where middle exon inclusion isincreased showed that such exons generally have weaker 5′ splice sites.

The CNN Model predictions of the present disclosure (combined with thefact that kinetin and analog Compound (I) are shown herein to promotethe recognition of ELP1 exon 20 through recruitment of U1 snRNP at the5′ splice site) strongly suggesting that small molecule compounds canact by promoting, either directly or indirectly, the recognition ofweakly defined exons.

Application of the CNN Model to all ClinVar pathogenic mutations thatdisrupt splicing, identified 214 human disease-causing mutations in 155unique genes as potential therapeutic targets of Compound (I), provingthat a deep learning model such as the CNN described herein provide apowerful approach to explore novel therapeutic targets for drugs thatmodify RNA splicing. As such, the treatment effect on splicing wasvalidated for several disease-causing mutations using patient cell linesand minigenes, and demonstrated the potential therapeutic feasibility oftargeting splicing in patients with cystic fibrosis (CFTR), cholesterolester storage disease (LIPA), Lynch syndrome (MLH1) and familialfrontotemporal dementia (MAPT), amongst others. These findings couldhave significant impact for patients carrying these mutations.

It will be appreciated that, although specific aspects have beendescribed herein for purposes of illustration, the present descriptionis not to be limited in scope by the specific illustrations and examplesherein disclosed. These illustrations and examples are intended tomerely represent several aspects of the invention. Any equivalentaspects of the illustrations and examples are also intended to be withinthe scope of the present description. Indeed, various modifications ofthe aspects of the illustrations and examples, in addition to thoseshown and described herein, will become apparent to those skilled in theart from the foregoing description, modification of which is intended tobe within the scope.

All references cited herein are incorporated herein by reference intheir entirety and for all purposes to the same extent as if eachindividual publication, patent or patent application was specificallyand individually indicated to be incorporated by reference in itsentirety for all purposes.

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What is claimed is:
 1. A compound for use in a method to modulate theproduction of one or more mature RNA isoforms from a gene transcript ina cell, wherein the method comprises, contacting the cell with thecompound, and wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,having the formula of Compound (I):


2. The compound for use in the method of claim 1, wherein the genetranscript is a wildtype gene transcript comprising, three exons and twointrons operably linked in the following order: Exon 1, Intron 1, Exon2, Intron 2, and Exon 3, and wherein a 5′ splice site of Exon 2comprises, a sequence selected from the group consisting of: CAAgtaagt(SEQ ID NO: 1), GATTAAgtgggt (SEQ ID NO: 2), CACTAGgtgaga (SEQ ID NO:3), and CCAgtgagga (SEQ ID NO: 4).
 3. The compound for use in the methodof claim 1, wherein the 5′ splice site of Exon 2 comprises, a sequenceselected from the group consisting of: CAAguaagu (SEQ ID NO: 5),GAUUAAgugggu (SEQ ID NO: 6), CACUAGgugaga (SEQ ID NO: 7), and CCAgugagga(SEQ ID NO: 8).
 4. The compound for use in the method of claim 1,wherein the gene transcript is a mutant gene transcript comprising,three exons and two introns operably linked in the following order: Exon1, Intron 1, Exon 2, Intron 2, and Exon 3, and wherein a 5′ splice siteof Exon 2 comprises, a sequence selected from the group consisting of:CAAgtaagc (SEQ ID NO: 9), GATTAAgtaggt (SEQ ID NO: 10), CACTAGgtgagc(SEQ ID NO: 11), CCAgttagga (SEQ ID NO: 12), AGCCAAgtatgt (SEQ ID NO:13), ATCCAAgtatgt (SEQ ID NO: 14), CTGAAgtcagt (SEQ ID NO: 15), andAGTgtaagta (SEQ ID NO: 16).
 5. The compound for use in the method ofclaim 1, wherein the 5′ splice site of Exon 2 comprises, a sequenceselected from the group consisting of: CAAguaagc (SEQ ID NO: 17),GAUUAAguaggu (SEQ ID NO: 18), CACUAGgugagc (SEQ ID NO: 19), CCAguuagga(SEQ ID NO: 20), AGCCAAguaugu (SEQ ID NO: 21), AUCCAAguaugu (SEQ ID NO:22), CUGAAgucagu (SEQ ID NO: 23), and AGUguaagua (SEQ ID NO: 24).
 6. Thecompound for use in the method of claim 1, wherein the gene transcriptis a predicted wildtype or mutant gene transcript in a cell comprising,a nucleotide sequence selected from the group consisting of: CTTAG (SEQID NO: 25), NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO: 27), CCCTT (SEQ IDNO: 28), TNNCT (SEQ ID NO: 29), GCAGA (SEQ ID NO: 30), TNTGA (SEQ ID NO:31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO:34), TTTTT (SEQ ID NO: 35), ATGGN (SEQ ID NO: 36), TCTCA (SEQ ID NO:37), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO: 39), GAGAG (SEQ ID NO:40), AGGAN (SEQ ID NO: 41), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO:43), GATTA (SEQ ID NO: 44), TCTTT (SEQ ID NO: 45), NNAGN (SEQ ID NO:46), TCGTG (SEQ ID NO: 47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO:49), AGACT (SEQ ID NO: 50), GGGTG (SEQ ID NO: 51), TTCCC (SEQ ID NO:52), AGTNA (SEQ ID NO: 53), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO:55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO:58), NTGTN (SEQ ID NO: 59), NTCCT (SEQ ID NO: 60), AACCT (SEQ ID NO:61), ACTCN (SEQ ID NO: 62), and CTGTA (SEQ ID NO: 63), and wherein Nrepresents any DNA nucleotide.
 7. The compound for use in the method ofclaim 1, wherein the gene transcript is a predicted wildtype or mutantgene transcript in a cell comprising, a nucleotide sequence selectedfrom the group consisting of: NNAGC (SEQ ID NO: 26), NCAGA (SEQ ID NO:27), CCCTT (SEQ ID NO: 28), TNNCT (SEQ ID NO: 29), TNTGA (SEQ ID NO:31), TGAGC (SEQ ID NO: 32), CTCTC (SEQ ID NO: 33), TNNNT (SEQ ID NO:34), TTTTT (SEQ ID NO: 35), AAGCT (SEQ ID NO: 38), GTCAT (SEQ ID NO:39), GAGAG (SEQ ID NO: 40), AGACC (SEQ ID NO: 42), AAGGT (SEQ ID NO:43), GATTA (SEQ ID NO: 44), NNAGN (SEQ ID NO: 46), TCGTG (SEQ ID NO:47), ANGAA (SEQ ID NO: 48), TTAAA (SEQ ID NO: 49), GGGTG (SEQ ID NO:51), TTCCC (SEQ ID NO: 52), TATGT (SEQ ID NO: 54), GGGAA (SEQ ID NO:55), NTGNN (SEQ ID NO: 56), NTCCC (SEQ ID NO: 57), CAGGC (SEQ ID NO:58), NTGTN (SEQ ID NO: 59), AACCT (SEQ ID NO: 61), and CTGTA (SEQ ID NO:63), and wherein N represents any DNA nucleotide.
 8. The compound foruse in the method of claim 1, wherein the gene transcript is a predictedwildtype or mutant gene transcript in a cell comprising, a nucleotidesequence selected from the group consisting of: CUUAG (SEQ ID NO: 64),NNAGC (SEQ ID NO: 65), NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67),UNNCU (SEQ ID NO: 68), UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71),CUCUC (SEQ ID NO: 72), UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74),AUGGN (SEQ ID NO: 75), UCUCA (SEQ ID NO: 76), AAGCU (SEQ ID NO: 77),GUCAU (SEQ ID NO: 78), AGGAN (SEQ ID NO: 80), AAGGU (SEQ ID NO: 82),GAUUA (SEQ ID NO: 83), UCUUU (SEQ ID NO: 84), NNAGN (SEQ ID NO: 85),UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87), UUAAA (SEQ ID NO: 88),AGACU (SEQ ID NO: 89), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91),AGUNA (SEQ ID NO: 92), UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95),NUCCC (SEQ ID NO: 96), NUGUN (SEQ ID NO: 98), NUCCU (SEQ ID NO: 99),AACCU (SEQ ID NO: 100), ACUCN (SEQ ID NO: 101), and CUGUA (SEQ ID NO:102), and wherein N represents any RNA nucleotide.
 9. The compound foruse in the method of claim 1, wherein the gene transcript is a predictedwildtype or mutant gene transcript in a cell comprising, a nucleotidesequence selected from the group consisting of: NNAGC (SEQ ID NO: 65),NCAGA (SEQ ID NO: 66), CCCUU (SEQ ID NO: 67), UNNCU (SEQ ID NO: 68),UNUGA (SEQ ID NO: 70), UGAGC (SEQ ID NO: 71), CUCUC (SEQ ID NO: 72),UNNNU (SEQ ID NO: 73), UUUUU (SEQ ID NO: 74), AAGCU (SEQ ID NO: 77),GUCAU (SEQ ID NO: 78), AAGGU (SEQ ID NO: 82), GAUUA (SEQ ID NO: 83),NNAGN (SEQ ID NO: 85), UCGUG (SEQ ID NO: 86), ANGAA (SEQ ID NO: 87),UUAAA (SEQ ID NO: 88), GGGUG (SEQ ID NO: 90), UUCCC (SEQ ID NO: 91),UAUGU (SEQ ID NO: 93), NUGNN (SEQ ID NO: 95), NUCCC (SEQ ID NO: 96),NUGUN (SEQ ID NO: 98), AACCU (SEQ ID NO: 100), and CUGUA (SEQ ID NO:102), and wherein N represents any RNA nucleotide.
 10. The compound foruse in the method of claim 1, wherein Compound (I) modulates exoninclusion or exon exclusion to produce one or more mature RNA isoformsfrom a gene transcript in a cell, and wherein the method comprisescontacting the cell with Compound (I).
 11. The compound for use in themethod of claim 1, wherein Compound (I) increases exon inclusion toproduce one or more mature RNA isoforms from a gene transcript in acell, and wherein the method comprises contacting the cell with Compound(I).
 12. The compound for use in the method of claim 1, wherein Compound(I) increases exon exclusion to produce one or more mature RNA isoformsfrom a gene transcript in a cell, and wherein the method comprisescontacting the cell with Compound (I).
 13. The compound for use in themethod of claim 1, wherein Compound (I) modulates exon inclusion or exonexclusion to produce one or more mature RNA isoforms from a genetranscript in a cell, and wherein the method comprises contacting thecell in vivo or in vitro with Compound (I).
 14. The compound for use inthe method of claim 1, wherein the method treats a disease associatedwith or mediated by a mutation in a gene transcript in a subject in needthereof comprising, administering Compound (I) to the subject, whereinexon inclusion or exon exclusion is modulated in one or more mature RNAisoforms produced from the gene transcript, and wherein the subject ishuman.
 15. The compound for use in the method of claim 1, wherein themethod treats a disease associated with or mediated by a mutation in awildtype gene transcript in a subject in need thereof comprising,administering Compound (I) to the subject, wherein exon inclusion orexon exclusion is modulated in one or more mature RNA isoforms producedfrom the gene transcript, and wherein one or more of the mature RNAisoforms produce a functional protein.
 16. A pharmaceutical compositioncomprising a compound and a pharmaceutically acceptable carrier,excipient, or diluent for use in a method of treating a diseaseassociated with or mediated by a mutation in a gene transcript in asubject in need thereof, wherein the compound is2-chloro-N-(pyridin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-aminehaving the formula of Compound (I):

wherein exon inclusion or exon exclusion is modulated in one or moremature RNA isoforms produced from a gene transcript in a cell.